WO2020086647A1 - Ny-eso-1 t cell receptors and methods of use thereof - Google Patents
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K39/46—Cellular immunotherapy
- A61K39/463—Cellular immunotherapy characterised by recombinant expression
- A61K39/4632—T-cell receptors [TCR]; antibody T-cell receptor constructs
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- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464484—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
- A61K39/464488—NY-ESO
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
- A61K2239/48—Blood cells, e.g. leukemia or lymphoma
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/50—Fusion polypeptide containing protease site
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2510/00—Genetically modified cells
Definitions
- the present disclosure is related to antigen-binding proteins that specifically bind to an HLA-displayed New York esophageal squamous cell carcinoma 1 (NY-ESO-1 ) peptide, and therapeutic and diagnostic methods of using those binding proteins.
- NY-ESO-1 New York esophageal squamous cell carcinoma 1
- T cell receptors are membrane bound heterodimers comprising an a and b chain resembling an immunoglobulin variable (V) and constant (C) region.
- the TOR a chain includes a covalently linked V-a and C-a chain, whereas the b chain includes a V-b chain covalently linked to a C-b chain.
- the V-a and V-b chains form a pocket or cleft that can bind an antigen in the context of a major histocompatibility complex (MHC) (known in humans as an HLA complex).
- MHC major histocompatibility complex
- TCRs are primary effectors of the immune system that have unique advantages as a platform for developing therapeutics. While antibody therapeutics are limited to recognition of pathogens in the blood and extracellular spaces, or to protein targets on the cell surface,
- T cell receptors can recognize antigens displayed with MHC molecules on the surface of cells, including antigens derived from intracellular proteins.
- TCRs can participate in controlling various immune responses. For instance, T cells are involved in regulation of the humoral immune response through induction of differentiation of B cells into antibody producing cells. In addition, activated T cells act to initiate cell-mediated immune responses. Thus, TCRs can recognize additional targets not available to antibodies.
- TCRs have been reported to mediate cell killing, increase B cell proliferation, and impact the development and severity of various disorders including cancer, allergies, viral infections and autoimmune disorders.
- TCRs In view of the function of TCRs, antigen-specific TCRs have been evaluated for use in immunotherapy for their ability to redirect T cells to tumors expressing the antigen. TCRs will bind to a small peptide, only 8-12 amino acids in length, which are bound on the surface of a target cell by the Major Histocompatibility Complex (MHC). TCRs can therefore recognize intracellular antigens derived from cancer or viral proteins because these antigens are processed and displayed as peptides in the context of the surface MHC. Hence, TCRs can recognize additional internal cell targets not available to antibodies or therapies that cannot penetrate the cell.
- MHC Major Histocompatibility Complex
- NY-ESO-1 or New York esophageal squamous cell carcinoma 1 is a well-known cancer-testis antigen (CTAs) with re-expression in numerous cancer types. Its ability to elicit spontaneous humoral and cellular immune responses, together with its restricted expression pattern, have rendered it a good candidate target for cancer immunotherapy.
- CTAs cancer-testis antigen
- the present invention provides T cell receptors (TCRs) that were generated against a NY-ESO-1 peptide antigen in the context of MHC (HLA-A2).
- TCRs T cell receptors
- HLA-A2 MHC
- the unique TCR sequences identified have shown specific binding to the small peptide NY-ESO-1 presented in the groove of an HLA molecule, and exhibited activation of T cells in a reporter assay.
- the present invention provides isolated T cell receptors (TCRs) that bind specifically to an HLA-A2 presented cancer testis antigen New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1 ) peptide comprising the amino acid sequence of SLLMWITQC (SEQ ID NO:1 1 1 ) (NY-ESO-1 (157-165)), wherein the TCR has a property selected from the group consisting of: (a) does not specifically bind to cells expressing predicted off-target peptides but not an HLA-A2 presented NY-ESO-1 peptide comprising the amino acid sequence of SEQ ID NO: 1 1 1 , as determined by luminescence assay; and (b) activates a T cell response two times greater than a patient-derived NY-ESO- 1 -specific TCR.
- TCRs T cell receptors
- the TCR activates a T cell response about two times greater, or about three times greater, or about four times greater than a patient-derived NY- ESO-1 -specific TCR as determined by a TCR-mediated T cell signaling luminescent bioassay.
- the TCR may include at least one TCR alpha chain variable domain and/or at least one beta chain variable domain.
- the TCR comprises a TCR alpha chain variable domain and a TCR beta chain variable domain.
- the alpha chain variable domain comprises complementary determining regions (CDR) 1 , CDR2, and CDR3, wherein the CDR3 region comprises the amino acid sequence of Formula I (SEQ ID NO: 1 18):
- N 2 is Leu, Tyr, Val, or Ala
- N 3 is Arg, Asn, Thr, or Ser
- N 4 is Pro, Ser, Glu, lie, Gly, Met, Lys, or Thr;
- N 5 which may or may not be present, is Lys
- N 6 which may or may not be present in Asp, Ala, Gly, Leu, or Asn;
- N 7 is Ser, Asn, Ala, Tyr, or Thr;
- N 8 which may or may not be present, is Ser or Gly
- N g which may or may not be present, is Gly
- N 10 which may or may not be present, is Gly or Ser;
- N which may or may not be present, is Trp, Gly, Ser, Gin, Ala, or Pro;
- N 12 is Gly, Tyr, Asn, Gin, or Ser;
- N 13 is Lys, Ala, Asp, lie, or Asn;
- N 14 is a nonpolar amino acid
- N 15 is Gin, Asn, Arg, Thr, Val, lie, or Ser.
- Ni is Ala or lie.
- N 14 is Phe, Leu,
- the beta chain variable domain comprises complementary determining regions (CDR) 1 , CDR2, and CDR3, wherein the CDR3 region comprises amino acid sequence of Formula II (SEQ ID NO: 1 19):
- Ni and N 2 are each independently Ala or Ser;
- N 3 is Ser, Met, or Lys
- N 4 is Tyr, Trp, His, Leu, Thr, Glu or Gin;
- N 5 is Ser, Ala, Thr, Gly, Val, or Arg;
- N 6 which may or may not be present, is Gly, His, Asp, Thr, Pro, Met, or Ser;
- N 7 which may or may not be present, is Gly, Tyr, Asn, or Pro;
- N 8 which may or may not be present, is Y;
- N g which may or may not be present, is N;
- N 10 which may or may not be present, is a polar amino acid
- N is Pro, Glu, Gly, or Asp
- N 12 which may or may not be present, is Glu
- N 13 is Leu, Ala, Gin, or Tyr
- N 14 is His, Phe, or Thr.
- N 10 is Ser, Thr, Gin, or Tyr.
- the CDR1 of the alpha chain variable domain comprises any one of the CDR1 amino acid sequences set forth in Table 1 and the CDR2 of the alpha chain variable domain independently comprises any one of the CDR2 amino acid sequences set forth in Table 1.
- the CDR1 of the beta chain variable domain comprises any one of the CDR1 amino acid sequences set forth in Table 1 and the CDR2 of the beta chain variable domain independently comprises any one of the CDR2 amino acid sequences set forth in Table 1.
- the isolated TCR comprises alpha chain variable domain CDR1 , CDR2 and CDR3 contained within any one of the alpha chain variable domain sequences listed in Table 3; and beta chain variable domain CDR1 , CDR2 and CDR3 contained within any one of the beta chain variable domain sequences listed in Table 3.
- the isolated TCR comprises an alpha chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the alpha chain variable domain amino acid sequences listed in Table 3.
- the isolated TCR comprises a beta chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the beta chain variable domain amino acid sequences listed in Table 3.
- the isolated TCR comprises: (a) an alpha chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the alpha chain variable domain amino acid sequences listed in Table 3; and (b) a beta chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the beta chain variable domain amino acid sequences listed in Table 3.
- the isolated TCR comprises
- an alpha chain variable domain CDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 15, 25, 35, 45, 55, 65, 75, 85, 95, and 105;
- an alpha chain variable domain CDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 16, 26, 36, 46, 56, 66, 76, 86, 96, and 106;
- a beta chain variable domain CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 , 1 1 , 21 , 31 , 41 , 51 , 61 , 71 , 81 , 91 , and 101 ;
- a beta chain variable domain CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 12, 22, 32, 42, 52, 62, 72, 82, 92, and 102;
- the isolated TCR comprises an alpha chain variable domain/beta chain variable domain amino acid sequence pair selected from the group consisting of SEQ ID NOs: 9/7; 19/17; 29/27; 39/37; 49/47; 59;57; 69/67; 79/77; 89/87; 99/97; and 109/107.
- the present invention also provides isolated TCRs that compete for binding to any of the isolated TCRs disclosed herein.
- the isolated TCRs of the invention further comprise a detectable moiety.
- the present invention further provides pharmaceutical compositions comprising the isolated TCR of the invention and a pharmaceutically acceptable carrier or diluent; and isolated cells presenting the TCR of the invention.
- the present invention provides an isolated polynucleotide molecule comprising a polynucleotide sequence that encodes an alpha chain variable domain of the isolated TCRs of the invention.
- the present invention provides an isolated polynucleotide molecule comprising a polynucleotide sequence that encodes a beta chain variable domain of the isolated TCRs of the invention.
- the present invention also provides vectors comprising the polynucleotide molecules of the invention; and cells expressing the vectors of the invention.
- the present invention provides a method of treating a subject having an NY-ESO-1 -associated disease or disorder, comprising administering to the subject a therapeutically effective amount of the isolated TCRs of the invention, the pharmaceutical compositions of the invention, or a plurality of the cells of the invention, thereby treating the subject.
- the NY-ESO-1 -associated disease or disorder is NY-ESO-1 - associated cancer, such as a liposarcoma, a neuroblastoma, a myeloma, a metastatic melanoma, a synovial sarcoma, a bladder cancer, an esophageal cancer, a hepatocellular cancer, a head and neck cancer, a non-small cell lung cancer, an ovarian cancer, a prostate cancer, a breast cancer, astrocytic tumor, glioblastoma multiforme, anaplastic astrocytoma, brain tumor, fallopian tube cancer, ovarian epithelial cancer, primary peritoneal cavity cancer, advanced solid tumors, soft tissue sarcoma, melanoma, a sarcoma, myelodysplastic syndrome, acute myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, Hod
- the NY-ESO-1 -associated cancer is a liposarcoma, a neuroblastoma, a myeloma, a metastatic melanoma, a synovial sarcoma, a bladder cancer, an esophageal cancer, a hepatocellular cancer, a head and neck cancer, a non-small cell lung cancer, an ovarian cancer, a prostate cancer, or a breast cancer.
- the isolated TCR, the pharmaceutical composition, or the plurality of cells is administered to the subject in combination with a second therapeutic agent.
- the isolated TCR, the pharmaceutical composition, or the plurality of cells is administered subcutaneously, intravenously, intradermally,
- the present invention provides an isolated nucleic acid molecule encoding a T cell receptor (TCR), wherein the TCR binds specifically to an HLA-A2 presented cancer testis antigen New York Esophageal Squamous Cell Carcinoma-1 (NY- ESO-1 ) peptide comprising the amino acid sequence of SLLMWITQC (SEQ ID NO:1 1 1 ) (NY-ESO-1 (157-165)), wherein the TCR has a property selected from the group consisting of: (a) does not specifically bind to cells expressing predicted off-target peptides but not an HLA-A2 presented NY-ESO-1 peptide comprising the amino acid sequence of SEQ ID NO:
- the TCR activates a T cell response about two times greater, or about three times greater, or about four times greater than a patient-derived NY- ESO-1 -specific TCR as determined by a TCR-mediated T cell signaling luminescent bioassay.
- the isolated nucleic acid molecule encodes at least one TCR alpha chain variable domain and/or at least one beta chain variable domain.
- the TCR comprises alpha chain variable domain
- CDR complementary determining regions
- the isolated TCR comprises alpha chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the alpha chain variable domain amino acid sequences listed in Table 3.
- the isolated TCR comprises beta chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the beta chain variable domain amino acid sequences listed in Table 3.
- the isolated TCR comprises (a) an alpha chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the alpha chain variable domain amino acid sequences listed in Table 3; and (b) a beta chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the beta chain variable domain amino acid sequences listed in Table 3.
- the isolated antigen-binding protein comprises [0081] (a) an alpha chain variable domain CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 14, 24, 34, 44, 54, 64, 74, 84, 94, and 104;
- an alpha chain variable domain CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 15, 25, 35, 45, 55, 65, 75, 85, 95, and 105;
- an alpha chain variable domain CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 16, 26, 36, 46, 56, 66, 76, 86, 96, and 106;
- a beta chain variable domain CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 , 1 1 , 21 , 31 , 41 , 51 , 61 , 71 , 81 , 91 , and 101 ;
- a beta chain variable domain CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 12, 22, 32, 42, 52, 62, 72, 82, 92, and 102;
- a beta chain variable domain CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 13, 23, 33, 43, 54, 63, 73, 83, 93, and 103.
- the isolated TCR comprises an alpha chain variable domain/beta chain variable domain amino acid sequence pair selected from the group consisting of SEQ ID NOs: 9/7; 19/17; 29/27; 39/37; 49/47; 59;57; 69/67; 79/77; 89/87; 99/97; and 109/107.
- the present invention also provides vectors comprising the isolated nucleic acid molecule of the invention; and isolated cells comprising the vectors of the invention.
- the present invention provides a method of treating a subject having a NY-ESO-1 -associated disease or disorder, comprising administering to the subject a plurality of the cells comprising the vectors of the invention, thereby treating the subject.
- the NY-ESO-1 -associated disease or disorder is NY-ESO-associated cancer.
- the NY-ESO-1 -associated cancer is a liposarcoma, a neuroblastoma, a myeloma, a metastatic melanoma, a synovial sarcoma, a bladder cancer, an esophageal cancer, a hepatocellular cancer, a head and neck cancer, a non-small cell lung cancer, an ovarian cancer, a prostate cancer, a breast cancer, astrocytic tumor, glioblastoma multiforme, anaplastic astrocytoma, brain tumor, fallopian tube cancer, ovarian epithelial cancer, primary peritoneal cavity cancer, advanced solid tumors, soft tissue sarcoma, melanoma, a sarcoma, myelodysplastic syndrome, acute myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, Hodgkin disease, multiple myeloma, synovi
- the NY-ESO-1 -associated cancer is a liposarcoma, a neuroblastoma, a myeloma, a metastatic melanoma, a synovial sarcoma, a bladder cancer, an esophageal cancer, a hepatocellular cancer, a head and neck cancer, a non-small cell lung cancer, an ovarian cancer, a prostate cancer, or a breast cancer.
- the plurality of cells is administered to the subject in combination with a second therapeutic agent.
- the present invention provides an isolated T cell receptor (TCR) that binds specifically to an HLA-A2 presented cancer testis antigen New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1 ) peptide comprising the amino acid sequence of SLLMWITQC (SEQ ID NO:1 1 1 ) (NY-ESO-1 (157-165)), wherein the TCR has a property selected from the group consisting of: (a) does not specifically bind to cells expressing predicted off-target peptides but not an HLA-A2 presented NY-ESO-1 peptide comprising the amino acid sequence of SEQ ID NO: 1 1 1 , as determined by luminescence assay; and (b) activates a T cell response having a signal to noise ratio greater than or equal to a patient-derived NY- ESO-1 -specific TCR as determined by a TCR-mediated T cell signaling luminescent bioassay.
- TCR T cell receptor
- the TCR activates a T cell response about two times greater, or about three times greater, or about four times greater than a patient-derived NY- ESO-1 -specific TCR as determined by a TCR-mediated T cell signaling luminescent bioassay.
- the TCR comprises at least one TCR alpha chain variable domain and/or at least one beta chain variable domain.
- the TCR comprises a TCR alpha chain variable domain and a TCR beta chain variable domain.
- the alpha chain variable domain comprises complementary determining regions (CDR) 1 , CDR2, and CDR3, wherein the CDR3 region comprises the amino acid sequence of Formula I:
- N 2 is Leu, Tyr, Val, or Ala
- N 3 is Arg, Asn, Thr, or Ser
- N 4 is Pro, Ser, Glu, lie, Gly, Met, Lys, or Thr;
- N 5 which may or may not be present, is Lys
- N 6 which may or may not be present in Asp, Ala, Gly, Leu, or Asn;
- N 7 is Ser, Asn, Ala, Tyr, or Thr;
- N 8 which may or may not be present, is Ser or Gly
- N g which may or may not be present, is Gly
- N 10 which may or may not be present, is Gly or Ser;
- N which may or may not be present, is Trp, Gly, Ser, Gin, Ala, or Pro;
- N 12 is Gly, Tyr, Asn, Gin, or Ser;
- N 13 is Lys, Ala, Asp, lie, or Asn;
- N 14 is a nonpolar amino acid
- N 15 is Gin, Asn, Arg, Thr, Val, lie, or Ser.
- Ni is Ala or lie.
- N 14 is Phe, Leu,
- the beta chain variable domain comprises
- CDR complementary determining regions
- Ni and N 2 are each independently Ala or Ser;
- N 3 is Ser, Met, or Lys
- N 4 is Tyr, Trp, His, Leu, Thr, Glu or Gin;
- N 5 is Ser, Ala, Thr, Gly, Val, or Arg;
- N 6 which may or may not be present, is Gly, His, Asp, Thr, Pro, Met, or Ser;
- N 7 which may or may not be present, is Gly, Tyr, Asn, or Pro;
- N 8 which may or may not be present, is Y;
- N g which may or may not be present, is N;
- N 10 which may or may not be present, is a polar amino acid
- N is Pro, Glu, Gly, or Asp
- N 12 which may or may not be present, is Glu
- N 13 is Leu, Ala, Gin, or Tyr
- N 14 is His, Phe, or Thr.
- N 10 is Ser, Thr, Gin, or Tyr.
- the CDR1 of the alpha chain variable domain comprises any one of the CDR1 amino acid sequences set forth in Table 1 and the CDR2 of the alpha chain variable domain
- the CDR1 of the beta chain variable domain comprises any one of the CDR1 amino acid sequences set forth in Table 1 and the CDR2 of the beta chain variable domain independently comprises any one of the CDR2 amino acid sequences set forth in Table 1.
- the isolated TCR comprises alpha chain variable domain CDR1 , CDR2 and CDR3 contained within any one of the alpha chain variable domain sequences listed in Table 3; and beta chain variable domain CDR1 , CDR2 and CDR3 contained within any one of the beta chain variable domain sequences listed in Table 3.
- the isolated TCR comprises an alpha chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the alpha chain variable domain amino acid sequences listed in Table 3. In some embodiments, the isolated TCR comprises a beta chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the beta chain variable domain amino acid sequences listed in Table 3.
- the isolated TCR comprises: (a) an alpha chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the alpha chain variable domain amino acid sequences listed in Table 3; and (b) a beta chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the beta chain variable domain amino acid sequences listed in Table 3.
- the isolated TCR comprises:
- an alpha chain variable domain CDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 16, 26, 36, 46, 56, 66, 76, 86, 96, and 106;
- a beta chain variable domain CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 , 1 1 , 21 , 31 , 41 , 51 , 61 , 71 , 81 , 91 , and 101 ;
- a beta chain variable domain CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 12, 22, 32, 42, 52, 62, 72, 82, 92, and 102;
- a beta chain variable domain CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 13, 23, 33, 43, 54, 63, 73, 83, 93, and 103.
- the isolated TCR comprises an alpha chain variable domain/beta chain variable domain amino acid sequence pair selected from the group consisting of SEQ ID NOs: 9/7; 19/17; 29/27; 39/37; 49/47; 59;57; 69/67; 79/77; 89/87; 99/97; and 109/107.
- the present disclosure provides an isolated TCR that competes for binding to an isolated TCR described above. In some embodiments, the present disclosure provides an isolated TCR that further comprises a detectable moiety.
- the present invention provides a pharmaceutical composition comprising an isolated TCR described above and a pharmaceutically acceptable carrier or diluent.
- the present invention provides an isolated cell presenting a TCR described above.
- the present invention provides a polynucleotide molecule comprising a polynucleotide sequence that encodes an alpha chain variable domain of an isolated TCR as described above.
- the present invention provides a polynucleotide molecule comprising a polynucleotide sequence that encodes a beta chain variable domain of an isolated TCR as described above.
- the present invention provides a vector comprising that polynucleotide molecule.
- the present invention provides a cell expressing that vector.
- the present invention provides a method of treating a subject having an NY-ESO-1 - associated disease or disorder, comprising administering to the subject a therapeutically effective amount of an isolated TCR, pharmaceutical composition, or plurality of cells as described above, thereby treating the subject.
- the NY-ESO-1 -associated disease or disorder is NY-ESO-1 - associated cancer.
- the NY-ESO-1 -associated cancer is a
- liposarcoma a neuroblastoma, a myeloma, a metastatic melanoma, a synovial sarcoma, a bladder cancer, an esophageal cancer, a hepatocellular cancer, a head and neck cancer, a non-small cell lung cancer, an ovarian cancer, a prostate cancer, a breast cancer, astrocytic tumor, glioblastoma multiforme, anaplastic astrocytoma, brain tumor, fallopian tube cancer, ovarian epithelial cancer, primary peritoneal cavity cancer, advanced solid tumors, soft tissue sarcoma, melanoma, a sarcoma, myelodysplastic syndrome, acute myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, Hodgkin disease, multiple myeloma, synovial sarcoma, metastatic solid tumors, esophageal cancer,
- the isolated TCR, the pharmaceutical composition, or the plurality of cells is administered to the subject in combination with a second therapeutic agent. In some embodiments, the isolated TCR, the pharmaceutical composition, or the plurality of cells is administered subcutaneously, intravenously, intradermally,
- the present invention provides a polynucleotide molecule encoding a T cell receptor (TCR), wherein the TCR binds specifically to an HLA-A2 presented cancer testis antigen New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1 ) peptide comprising the amino acid sequence of SLLMWITQC (SEQ ID NO:1 1 1 ) (NY-ESO-1 (157-165)), wherein the TCR has a property selected from the group consisting of: (a) does not specifically bind to cells expressing predicted off-target peptides but not an HLA-A2 presented NY-ESO-1 peptide comprising the amino acid sequence of SEQ ID NO: 1 1 1 , as determined by luminescence assay; and (b) activates a T cell response about two times greater than a patient-derived NY-ESO-1 -specific TCR as determined by a TCR-mediated T cell signaling luminescent bioassay.
- TCR T cell receptor
- the polynucleotide molecule encodes at least one TCR alpha chain variable domain and/or at least one beta chain variable domain.
- the TCR comprises alpha chain variable domain complementary determining regions (CDR) 1 , CDR2, and CDR3 contained within any one of the alpha chain variable domain sequences listed in Table 3; and beta chain variable domain CDR1 , CDR2 and CDR3 contained within any one of the beta chain variable domain sequences listed in Table 3.
- the isolated TCR comprises alpha chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the alpha chain variable domain amino acid sequences listed in Table 3.
- the isolated TCR comprises beta chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the beta chain variable domain amino acid sequences listed in Table 3.
- the isolated TCR comprises (a) an alpha chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the alpha chain variable domain amino acid sequences listed in Table 3; and (b) a beta chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the beta chain variable domain amino acid sequences listed in Table 3.
- the isolated antigen-binding protein comprises
- an alpha chain variable domain CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 15, 25, 35, 45, 55, 65, 75, 85, 95, and 105;
- an alpha chain variable domain CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 16, 26, 36, 46, 56, 66, 76, 86, 96, and 106;
- a beta chain variable domain CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 , 1 1 , 21 , 31 , 41 , 51 , 61 , 71 , 81 , 91 , and 101 ;
- a beta chain variable domain CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 12, 22, 32, 42, 52, 62, 72, 82, 92, and 102;
- a beta chain variable domain CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 13, 23, 33, 43, 54, 63, 73, 83, 93, and 103.
- the isolated TCR comprises an alpha chain variable domain/beta chain variable domain amino acid sequence pair selected from the group consisting of SEQ ID NOs: 9/7; 19/17; 29/27; 39/37; 49/47; 59;57; 69/67; 79/77; 89/87;
- the present invention provides a vector comprising the polynucleotide molecule as described above.
- the present invention provides an isolated cell comprising that vector.
- the invention provides a method of treating a subject having a NY-ESO-1 -associated disease or disorder, comprising administering to the subject a plurality of those cells, thereby treating the subject.
- the NY-ESO-1 -associated disease or disorder is NY-ESO-associated cancer.
- the NY-ESO-associated cancer is a liposarcoma, a neuroblastoma, a myeloma, a metastatic melanoma, a synovial sarcoma, a bladder cancer, an esophageal cancer, a hepatocellular cancer, a head and neck cancer, a non-small cell lung cancer, an ovarian cancer, a prostate cancer, a breast cancer, astrocytic tumor, glioblastoma multiforme, anaplastic astrocytoma, brain tumor, fallopian tube cancer, ovarian epithelial cancer, primary peritoneal cavity cancer, advanced solid tumors, soft tissue sarcoma, melanoma, a sarcoma, myelodysplastic syndrome, acute myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, Hodgkin disease, multiple myeloma, synovial sarcoma
- the present invention provides a T cell receptor (TCR) that binds specifically to an HLA-A2 presented cancer testis antigen New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1 ) peptide comprising the amino acid sequence of SLLMWITQC (SEQ ID NO:1 1 1 ) (NY-ESO-1 (157-165)), wherein the TCR comprises a complementary determining region 3 (CDR3) contained with an alpha chain variable domain of any one of SEQ ID NOs: 9, 19, 29, 39, 49, 59, 69, 79, 89, 99, and 109.
- TCR T cell receptor
- the present invention provides a T cell receptor (TCR) that binds specifically to an HLA-A2 presented cancer testis antigen New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1 ) peptide comprising the amino acid sequence of SLLMWITQC (SEQ ID NO:1 1 1 ) (NY-ESO-1 (157-165)), wherein the TCR comprises a complementary determining region 3 (CDR3) contained within a beta chain variable domain of any one of SEQ ID NOs: 7, 17, 27, 37, 47, 57, 67, 77, 87, 97, and 107.
- TCR T cell receptor
- the alpha chain variable domain further comprises a CDR1 and a CDR2, wherein the CDR1 comprises any one of the alpha chain variable domain CDR1 amino acid sequences set forth in Table 1 and the CDR2 independently comprises any one of the alpha chain variable domain CDR2 amino acid sequences set forth in Table 1 .
- the beta chain variable domain further comprises a CDR1 and a CDR2, wherein the CDR1 comprises any one of the beta chain variable CDR1 amino acid sequences set forth in Table 1 and the CDR2 independently comprises any one of the beta chain variable domain CDR2 amino acid sequences set forth in Table 1.
- the TCR comprises at least one TCR alpha chain variable domain and/or at least one beta chain variable domain. In some embodiments, the TCR comprises a TCR alpha chain variable domain and a TCR beta chain variable domain. In some embodiments, the TCR comprises alpha chain variable domain CDR1 , CDR2 and CDR3 contained within any one of the alpha chain variable domain amino acid sequences listed in Table 3; and beta chain variable domain CDR1 , CDR2 and CDR3 contained within any one of the beta chain variable domain amino acid sequences listed in Table 3.
- the TCR comprises an alpha chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the alpha chain variable domain amino acid sequences listed in Table 3.
- the TCR comprises a beta chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the beta chain variable domain amino acid sequences listed in Table 3.
- the TCR comprises: (a) an alpha chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the alpha chain variable domain amino acid sequences listed in Table 3; and (b) a beta chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the beta chain variable domain amino acid sequences listed in Table 3.
- the TCR comprises:
- an alpha chain variable domain CDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 15, 25, 35, 45, 55, 65, 75, 85, 95, and 105;
- an alpha chain variable domain CDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 16, 26, 36, 46, 56, 66, 76, 86, 96, and 106;
- a beta chain variable domain CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 , 1 1 , 21 , 31 , 41 , 51 , 61 , 71 , 81 , 91 , and 101 ;
- a beta chain variable domain CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 12, 22, 32, 42,52, 62, 72, 82, 92, and 102;
- the TCR comprises an alpha chain variable domain/beta chain variable domain amino acid sequence pair selected from the group consisting of SEQ ID NOs: 9/7, 19/17, 29/27, 39/37, 49/47, 59/57, 69/67, 79/77, 89/87, 99/97, and 109/107.
- the TCR further comprises a detectable moiety.
- the TCR has an on-target binding/off-target binding value of greater than 5, greater than 10, greater than 15, greater than 20, greater than 50, greater than 100, greater than 200, greater than 300, greater than 400, greater than 500, greater than 600, greater than 700, greater than 800, greater than 900, or greater than 1000. In some embodiments, the TCR has an on-target binding/off-target binding value of greater than 10. In some embodiments, the TCR has an on-target binding/off-target binding value of greater than 500.
- the present invention provides a TCR that competes for binding to TCR as described above.
- the present invention provides a pharmaceutical composition comprising a TCR as described herein and a pharmaceutically acceptable carrier or diluent.
- the present invention provides an isolated cell presenting a TCR as described herein.
- the present invention provides a polynucleotide molecule comprising a polynucleotide sequence that encodes an alpha chain variable domain of a TCR described herein.
- the present invention provides a polynucleotide molecule comprising a polynucleotide sequence that encodes a beta chain variable domain of a TCR as described herein.
- the present invention provides a vector comprising the alpha chain or beta chain polynucleotide sequence.
- the present invention provides an isolated cell expressing that vector.
- the present invention provides a method of treating a subject having an NY-ESO-1 - associated disease or disorder, comprising administering to the subject a therapeutically effective amount of a TCR as described herein, a pharmaceutical composition as described herein, or an isolated cell as described herein, thereby treating the subject.
- the NY-ESO-1 -associated disease or disorder is NY-ESO-1 - associated cancer.
- the NY-ESO-1 -associated cancer is a
- liposarcoma a neuroblastoma, a myeloma, a metastatic melanoma, a synovial sarcoma, a bladder cancer, an esophageal cancer, a hepatocellular cancer, a head and neck cancer, a non-small cell lung cancer, an ovarian cancer, a prostate cancer, a breast cancer, astrocytic tumor, glioblastoma multiforme, anaplastic astrocytoma, brain tumor, fallopian tube cancer, ovarian epithelial cancer, primary peritoneal cavity cancer, advanced solid tumors, soft tissue sarcoma, melanoma, a sarcoma, myelodysplastic syndrome, acute myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, Hodgkin disease, multiple myeloma, synovial sarcoma, metastatic solid tumors, esophageal cancer,
- the present invention provides a polynucleotide molecule encoding a T cell receptor (TCR), wherein the TCR binds specifically to an HLA-A2 presented cancer testis antigen NY-ESO-1 peptide comprising the amino acid sequence of SLLMWITQC (SEQ ID NO:1 1 1 ) (NY-ESO-1 (157-165)), wherein the TCR has a property selected from the group consisting of: (a) does not specifically bind to cells expressing predicted off-target peptides but not an HLA-A2 presented NY-ESO-1 peptide comprising the amino acid sequence of SEQ ID NO: 1 1 1 , as determined by luminescence assay; (b) does not bind to cells expressing predicted off-target peptides as determined by a flow cytometry assay; (c) activates a T cell response about two times greater than a patient-derived NY-ESO-1 - specific TOR as determined by a TCR-mediated T cell signaling luminescent bioas
- the polynucleotide molecule encodes at least one TCR alpha chain variable domain and/or at least one beta chain variable domain.
- the TCR comprises alpha chain variable domain complementary determining regions (CDR) 1 , CDR2, and CDR3 contained within any one of the alpha chain variable domain sequences listed in Table 3; and beta chain variable domain CDR1 , CDR2 and CDR3 contained within any one of the beta chain variable domain sequences listed in Table 3.
- the TCR comprises an alpha chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the alpha chain variable domain amino acid sequences listed in Table 3.
- the TCR comprises a beta chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the beta chain variable domain amino acid sequences listed in Table 3.
- the TCR comprises (a) an alpha chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the alpha chain variable domain amino acid sequences listed in Table 3; and (b) a beta chain variable domain having an amino acid sequence that has at least 85% amino acid identity to the entire amino acid sequence of any one of the amino acid sequences of the beta chain variable domain amino acid sequences listed in Table 3.
- the TCR comprises
- an alpha chain variable domain CDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 15, 25, 35, 45, 55, 65, 75, 85, 95, and 105;
- a beta chain variable domain CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 12, 22, 32, 42, 52, 62, 72, 82, 92, and 102;
- a beta chain variable domain CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 13, 23, 33, 43, 53, 63, 73, 83, 93, and 103.
- the TCR comprises an alpha chain variable domain/beta chain variable domain amino acid sequence pair selected from the group consisting of SEQ ID NOs: 9/7, 19/17, 29/27, 39/37, 49/47, 59/57, 69/67, 79/77, 89/87, 99/97, and 109/107.
- the TCR comprises
- a beta chain variable domain CDR1 encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 121 , 127, 133, 140, 142, 150, and 153;
- a beta chain variable domain CDR2 encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 122, 128, 143, 151 , and 154;
- a beta chain variable domain CDR3 encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 123, 129, 134, 136, 141 , 144, 148, 152, 155, 159.
- the TCR comprises an alpha chain variable domain/beta chain variable domain nucleic acid sequence pair selected from the group consisting of SEQ ID NOs: 10/8, 20/18, 30/28, 40/38, 50/48, 60/58, 70/68, 80/78, 90/88, 100/98, and 1 10/108.
- the present invention provides a vector comprising the polynucleotide sequence of a polynucleotide molecule described herein.
- the present invention provides an isolated cell comprising that vector.
- the present invention provides a method of treating a subject having an NY-ESO-1 -associated disease or disorder, comprising administering to the subject that cell.
- the NY-ESO-1 -associated disease or disorder is NY-ESO-1 - associated cancer.
- the NY-ESO-1 -associated cancer is a liposarcoma, a neuroblastoma, a myeloma, a metastatic melanoma, a synovial sarcoma, a bladder cancer, an esophageal cancer, a hepatocellular cancer, a head and neck cancer, a non-small cell lung cancer, an ovarian cancer, a prostate cancer, a breast cancer, astrocytic tumor, glioblastoma multiforme, anaplastic astrocytoma, brain tumor, fallopian tube cancer, ovarian epithelial cancer, primary peritoneal cavity cancer, advanced solid tumors, soft tissue sarcoma, melanoma, a sarcoma, myelodysplastic syndrome, acute myeloid leukemia, Flodgkin lymphoma, non-Flodgkin lymphoma, Flodgkin disease, multiple myeloma, synovial
- a cell as described herein is a primary cell, such as a primary lymphocyte (e.g., a primary T lymphocyte).
- a primary lymphocyte e.g., a primary T lymphocyte
- FIG. 1 depicts the activity of the indicated TCRs as determined by luminescence assay.
- Reporter T cells expressing HLA-A2/NY-ESO-1 (157-165) specific TCRs were co cultured with HLA-A2+ APCs presenting the NY-ESO-1 peptide.
- VelociTTM derived TCRs activated T cells stronger than the patient-derived NY-ESO specific 1 G4 control TCR.
- FIG. 2 A, FIG. 2B, FIG. 2C, FIG. 2D, and FIG. 2E depict the specificity of the indicated TCRs as determined by luminescence assay.
- FIG. 2A shows specificity with respect to the EARS2:306-313 off-target peptide.
- FIG. 2B shows specificity with respect to the MAGEH1 :90-98 off-target peptide.
- FIG. 2C shows specificity with respect to the
- FIG. 2D shows specificity with respect to the URB1 :1853- 1861 off-target peptide.
- FIG. 2E shows specificity with respect to the LV9-5 mucin off-target peptide.
- Figures 2A-2E disclose SEQ ID NOs : 1 1 1 , 1 14, 1 1 1 , 1 15, 1 1 1 , 1 16, 1 1 1 , 1 17, 1 1 1 and 120, respectively, in order of appearance.
- FIG. 3 depicts a TCR construct design used for expressing the TCR001 construct in primary T cells.
- FIV denotes the human variable domain and MC denotes the mouse constant domain for each respective TCR chain.
- the EF1 a promoter is shown as an arrow, and a furin cleavage site is denoted by a solid black box.
- FIG. 4 depicts a loss of endogenous TCR expression following electroporation with sgRNA targeting the TRAC locus and TRBC1/2 loci. T cells were stained with anti-human CD3 to assess cell surface TCR expression.
- FIG. 5A and FIG. 5B depict dextramer staining data for the detection of antigen specific T cells recognizing NY-ESO-1 157-165 peptide presented by FILA-A2.
- FIG. 5A shows data at Day 9 of expansion pre-sorting and immediately post-sorting.
- FIG. 5B shows data following expansion for 12 days post-sorting.
- FIG. 6 depicts cytotoxicity data showing that T cells expressing TCR001 lyse target cells that express endogenous levels of NY-ESO-1 (IM9) or overexpress a single chain FILA- A2 carrying NY-ESO-1 (157-165) peptide (IM9 ++ ). K562 cells lacking NY-ESO-1 expression were used to ensure that TCR mediated killing was antigen dependent. Untransduced and expanded T cells failed to kill any target cell, indicating that expression of TCR001 was necessary for target cell lysis.
- IM9 NY-ESO-1
- the present invention provides T cell receptors (TCRs) that were generated against an NY-ESO-1 peptide antigen in the context of MHC (HLA-A2).
- TCRs T cell receptors
- HLA-A2 MHC
- the unique TCR sequences identified have shown specific binding to the small peptide NY-ESO-1 presented in the groove of an HLA molecule and exhibited activation of T cells in a reporter assay.
- phrases such as“one embodiment” or“an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the invention.
- the appearances of phrases such as“in one embodiment” in various places in the specification are not necessarily all referring to the same embodiment.
- the articles“a” and“an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
- “an element” means one element or more than one element.
- the term“comprising” or“comprises” is used herein in reference to compositions, methods, and respective component(s) thereof, that are essential to the disclosure, yet open to the inclusion of unspecified elements, whether essential or not.
- T cell receptor refers to an immunoglobulin superfamily member having a variable binding domain, a constant domain, a
- transmembrane region and a short cytoplasmic tail; see, e.g., Janeway et al.,
- a TCR can be found on the surface of a cell and generally is comprised of a heterodimer having a and b chains (also known as TCRa and T ⁇ Rb, respectively), or g and d chains (also known as TCRy and TCR6, respectively).
- the extracellular portion of TCR chains ⁇ e.g., a-chain, b-chain
- TCR chains ⁇ e.g., a-chain, b-chain
- a variable region ⁇ e.g., TCR variable a region or Va and TCR variable b region or nb; typically amino acids 1 to 1 16 based on Kabat numbering at the N-terminus
- one constant region ⁇ e.g., TCR constant domain a or Ca and typically amino acids 1 17 to 259 based on Kabat, TCR constant domain b or ⁇ b, typically amino acids 1 17 to 295 based on Kabat
- the variable domains contain complementary determining regions (CDRs) separated by framework regions (FRs).
- a TCR is found on the surface of T cells (or T lymphocytes) and associates with the CD3 complex.
- the source of a TCR of the present disclosure may be from various animal species, such as a human, mouse, rat, rabbit or other mammal.
- the source of a TCR of the present invention is a mouse genetically engineered to produce TCRs comprising human alpha and beta chains (see, e.g., PCT Publication No. WO 2016/164492, the entire contents of which is incorporated herein by reference).
- variable region (variable region of an alpha chain (Va), variable region of a beta chain (nb)) as used herein denotes each of the alpha and beta chains which is involved directly in binding the TCR to the antigen.
- The“constant region” of the alpha chain and of the beta chain are not involved directly in binding of a TCR to an antigen, but exhibit various effector functions.
- antigen as used herein is meant any substance that causes the immune system to produce antibodies or specific cell-mediated immune responses against it.
- a disease-associated antigen is any substance that is associated with any disease that causes the immune system to produce antibodies or a specific-cell mediated response against it.
- the term“NY-ESO-1” or“New York esophageal squamous cell carcinoma 1” refers to the well-known cancer-testis antigen (CTAs) that is re-expressed in numerous cancer types.
- nucleotide and amino acid sequence of full-length NY-ESO-1 is provided in GenBank as accession number NM 001327.2 (SEQ ID NOs:1 12 and 1 13, respectively). Numbering of particular NY-ESO-1 nucleotide bases and amino acids is with respect to SEQ ID NOs: 1 12 or 1 13, respectively, or to a corresponding location in another NY-ESO-1 sequence (e.g., a sequence aligned with SEQ ID NO: 1 12 or 1 13). As used herein, numbering can be indicated in parentheses (e.g., NY-ESO-1 (157-165)), subscript (e.g., NY- ESO-1157-165), or other formats indicating numbering.
- parentheses e.g., NY-ESO-1 (157-165)
- subscript e.g., NY- ESO-1157-165
- NY-ESO-1 includes recombinant NY-ESO-1 or a fragment thereof.
- the term also encompasses NY-ESO-1 or a fragment thereof coupled to, for example, histidine tag, mouse or human Fc, or a signal sequence such as ROR1 .
- the term comprises NY-ESO-1 or a fragment thereof in the context of HLA-A2, linked to HLA-A2 or as displayed by HLA-A2.
- HLA refers to the human leukocyte antigen (HLA) system or complex, which is a gene complex encoding the major histocompatibility complex (MHC) proteins in humans. These cell-surface proteins are responsible for the regulation of the immune system in humans. HLAs corresponding to MHC class I (A, B, and C) present peptides from inside the cell.
- HLA human leukocyte antigen
- MHC major histocompatibility complex
- HLA-A refers to the group of human leukocyte antigens (HLA) that are coded for by the HLA-A locus.
- HLA-A is one of three major types of human MHC class I cell surface receptors.
- the receptor is a heterodimer, and is composed of a heavy a chain and smaller b chain.
- the a chain is encoded by a variant HLA-A gene, and the b chain (b2- microglobulin) is an invariant b2 microglobulin molecule.
- HLA-A2 (which may also be referred to as HLA-A * 0201 or HLA-A * 02:01 ) is one particular class I major histocompatibility complex (MHC) allele group at the HLA-A locus; the a chain is encoded by the HLA-A * 02 gene and the b chain is encoded by the b2- microglobulin or B2M locus.
- MHC major histocompatibility complex
- TCR forms a complex with an antigen that is relatively stable under physiologic conditions.
- Specific binding can be characterized by an equilibrium dissociation constant of at least about 1 x10 6 M or less, for example, 1 x10 8 M or less (e.g., a smaller K D denotes a tighter binding).
- Methods for determining whether two molecules specifically bind are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like.
- the TCRs of the invention bind specifically to an HLA-A2 presented cancer testis antigen New York Esophageal Squamous Cell Carcinoma-1 (NY- ESO-1 ) peptide, e.g., a peptide comprising amino acid residues 157-165 of NY-ESO-1 .
- off-target peptide refers to a peptide that differs by 1 , 2, 3, 4, 5 or more amino acids from a target peptide ⁇ e.g., NY-ESO-1 (157-165) peptide).
- a target peptide e.g., NY-ESO-1 (157-165) peptide.
- the term includes a peptide that differs by less than or equal to 3 amino acids than the target peptide. For example, for a 9-mer peptide, if 1 , 2, or 3 amino acids are not identical to the target peptide, it is considered an“off-target” peptide. In certain
- amino acid identity is expressed in terms of‘degree of similarity’ (DoS). If 6 or more amino acids within a 9-mer peptide are identical, the DoS is 6. In certain embodiments, a peptide with DoS ⁇ 6 is considered an“off-target” peptide.
- the term“off-target” peptide also refers to a peptide that is similar to the target peptide based on sequence homology, is predicted to bind to HLA-A2 and is comprised in a protein that is expressed in essential, normal tissues.
- a TCR of the present disclosure can bind to an HLA-A2-presented NY-ESO-1 peptide (e.g., a peptide comprising amino acid residues 157-165 of NY-ESO-1 ) with an affinity corresponding to a K D value that is at least ten-fold lower than its affinity for binding to an off-target peptide.
- an HLA-A2-presented NY-ESO-1 peptide e.g., a peptide comprising amino acid residues 157-165 of NY-ESO-1
- isolated refers to a composition, compound, substance, or molecule altered by the hand of man from the natural state.
- a composition or substance that occurs in nature is isolated if it has been changed or removed from its original environment, or both.
- a polynucleotide or a polypeptide naturally present in a living animal is not isolated, but the same polynucleotide or polypeptide separated from the coexisting materials of its natural state is isolated, as the term is employed herein.
- recombinant refers to TCRs of the invention created, expressed, isolated or obtained by technologies or methods known in the art as recombinant DNA technology which include, e.g., DNA splicing and transgenic expression.
- the term refers to TCRs expressed in a non-human mammal (including transgenic non-human mammals, e.g., transgenic mice), or a cell ⁇ e.g., CFIO cells) expression system or isolated from a recombinant combinatorial human antibody library.
- polynucleotide and“nucleic acid molecule” are used interchangeably to refer to polymeric forms of nucleotides of any length.
- the polynucleotides may contain deoxyribonucleotides, ribonucleotides, and/or their analogs.
- Nucleotides may have any three-dimensional structure, and may perform any function, known or unknown.
- polynucleotide includes, for example, single-, double-stranded and triple helical molecules, a gene or gene fragment, exons, introns, mRNA, tRNA, rRNA, ribozymes, antisense molecules, cDNA, recombinant polynucleotides, branched polynucleotides, aptamers, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers.
- a nucleic acid molecule may also comprise modified nucleic acid molecules ⁇ e.g., comprising modified bases, sugars, and/or internucleotide linkers).
- polypeptide is meant to refer to any polymer preferably consisting essentially of any of the 20 natural amino acids regardless of its size.
- protein is often used in reference to relatively large proteins, and“peptide” is often used in reference to small polypeptides, use of these terms in the field often overlaps.
- polypeptide refers generally to proteins, polypeptides, and peptides unless otherwise noted.
- Peptides useful in accordance with the present disclosure in general will be generally between about 0.1 to 100 kDa or greater up to about 1000 kDa, preferably between about 0.1 , 0.2, 0.5, 1 , 2, 5, 10, 20, 30 and 50 kDa as judged by standard molecule sizing techniques such as centrifugation or SDS-polyacrylamide gel electrophoresis.
- vector is a nucleic acid molecule that is able to replicate autonomously in a host cell and can accept foreign DNA.
- a vector carries its own origin of replication, one or more unique recognition sites for restriction endonucleases which can be used for the insertion of foreign DNA, and usually selectable markers such as genes coding for antibiotic resistance, and often recognition sequences ( e.g ., promoter) for the expression of the inserted DNA.
- Common vectors include plasmid vectors and phage vectors.
- TCRs of the invention may be conjugated to a moiety such as a ligand, a detectable moiety, or a therapeutic moiety (“immunoconjugate”), such as a cytotoxin, an anti-cancer drug, or any other therapeutic moiety useful for treating a disease or condition including NY-ESO-1 -associated disease or disorder, such as an NY-ESO-1 - associated cancer.
- a moiety such as a ligand, a detectable moiety, or a therapeutic moiety (“immunoconjugate”), such as a cytotoxin, an anti-cancer drug, or any other therapeutic moiety useful for treating a disease or condition including NY-ESO-1 -associated disease or disorder, such as an NY-ESO-1 - associated cancer.
- surface plasmon resonance refers to an optical phenomenon that allows for the analysis of real-time biomolecular interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIACORETM system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.).
- KD also known as K D or K d
- K D measurements are particularly useful for assessing protein-protein interactions, e.g. as in an antigen-binding protein-antigen interaction.
- the smaller the value of the KD the greater (or e.g. stronger) the binding interaction or affinity between the antigen-binding protein and antigen (e.g. target).
- the larger the value of the KD the weaker the binding interaction or affinity between the antigen-binding protein and antigen.
- nucleic acid molecule having substantial identity to a reference nucleic acid molecule may, in certain instances, encode a polypeptide having the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.
- Sequence identity can be calculated using an algorithm, for example, the
- Needleman Wunsch algorithm (Needleman and Wunsch 1970, J. Mol. Biol. 48: 443-453) for global alignment, or the Smith Waterman algorithm (Smith and Waterman 1981 , J. Mol. Biol. 147: 195-197) for local alignment.
- Another preferred algorithm is described by Dufresne et al in Nature Biotechnology in 2002 (vol. 20, pp. 1269-71 ) and is used in the software
- the term“substantial similarity” or“substantially similar” means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 90% sequence identity, even more preferably at least 95%, 96%, 97%, 98% or 99% sequence identity.
- residue positions, which are not identical differ by conservative amino acid substitutions.
- a “conservative amino acid substitution” is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g ., charge or hydrophobicity).
- R group side chain
- a conservative amino acid substitution will not substantially change the functional properties of a protein.
- the percent or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well known to those of skill in the art.
- Examples of groups of amino acids that have side chains with similar chemical properties include 1 ) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; 2) aliphatic-hydroxyl side chains: serine and threonine; 3) amide-containing side chains:
- Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine- tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine.
- a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256: 1443 45, herein incorporated by reference.
- A“moderately conservative” replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.
- GCG software contains programs such as GAP and BESTFIT which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof.
- FASTA e.g., FASTA2 and FASTA3
- FASTA3 provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (2000) supra).
- Sequences also can be compared using the Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 2, BLOSUM matrix of 62.
- Another preferred algorithm when comparing a sequence of the invention to a database containing a large number of sequences from different organisms is the computer program BLAST, especially BLASTP or TBLASTN, using default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215: 403-410 and (1997) Nucleic Acids Res. 25:3389-3402, each of which is herein incorporated by reference.
- A“patient-derived TCR” is a TCR that is produced by isolating the alpha and beta chains of an NY-ESO-1 reactive TCR isolated from the T-lymphocytes that mediated in vivo regression of a tumor in a subject having an NY-ESO-1 -associated cancer.
- An exemplary patient-derived NY-ESO-1 TCR is referred to as 1 G4 (see, e.g., U.S. Patent No. 8,143,376, the entire contents of which are incorporated herein by reference).
- the term“activates a T cell response having a signal to noise ratio stronger or equal to a patient-derived NY-ESO-1 -specific TCR” is meant to refer to an increase, i.e., about 2-fold or more, an amplification, i.e., about 2-fold, an augmentation, i.e., about 2-fold, or a boost of a physiological activity, i.e., about 2-fold, i.e., T cell signaling, as measured by, for example, a luminescent bioassay as described in Example 2.
- Reference to a greater T cell response, or a stronger T cell response or an activation signal, may be used
- the phrase“therapeutically effective amount” is meant an amount that produces the desired effect for which it is administered. The exact amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).
- the term“effective amount” is intended to encompass contexts such as a pharmaceutically effective amount or therapeutically effective amount.
- the effective amount is capable of achieving a beneficial state, beneficial outcome, functional activity in a screening assay, or improvement of a clinical condition.
- the term“subject” refers to an animal, preferably a mammal, in need of amelioration, prevention and/or treatment of an NY-ESO-1 -associated disease or disorder, such as an NY-ESO-1 -associated cancer (e.g ., an NY-ESO-1 -positive cancer).
- an NY-ESO-1 -associated cancer e.g ., an NY-ESO-1 -positive cancer.
- the term includes human subjects who have or are at risk of having an NY-ESO-1 -associated disease or disorder, such as an n NY-ESO-1 -associated cancer.
- anti-cancer drug means any agent useful to treat or ameliorate or inhibit cancer including, but not limited to, cytotoxins and agents such as antimetabolites, alkylating agents, anthracyclines, antibiotics, antimitotic agents, procarbazine, hydroxyurea, asparaginase, corticosteroids, cyclophosphamide, mytotane (0,P'-(DDD)), biologies (e.g., antibodies and interferons) and radioactive agents.
- cytotoxins such as antimetabolites, alkylating agents, anthracyclines, antibiotics, antimitotic agents, procarbazine, hydroxyurea, asparaginase, corticosteroids, cyclophosphamide, mytotane (0,P'-(DDD)), biologies (e.g., antibodies and interferons) and radioactive agents.
- cytotoxins such as antimetabolites, alkylating agents, anthracyclines, antibiotics, anti
- Taxol® paclitaxel
- temozolamide cytochalasin B
- gramicidin D ethidium bromide
- emetine cisplatin
- mitomycin etoposide
- tenoposide vincristine, vinbiastine
- coichicin doxorubicin
- daunorubicin daunorubicin, dihydroxy anthracin dione
- mitoxantrone mithramycin
- actinomycin D 1 -dehydrotestosterone
- glucocorticoids procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof.
- the terms“prevent”,“preventing”,“prevention”,“prophylactic treatment” and the like are meant to refer to reducing the probability of developing a disorder or condition in a subject, who does not have, but is at risk of or susceptible to developing a disorder or condition. Prevention and the like do not mean preventing a subject from ever getting the specific disease or disorder. Prevention may require the administration of multiple doses. Prevention can include the prevention of a recurrence of a disease in a subject for whom all disease symptoms were eliminated, or prevention of recurrence in a relapsing-remitting disease.
- TCRs NY-ESO-1 T Cell Receptors
- Compositions Comprising NY-ESO-1 TCRs
- T cells are a subgroup of cells which, together with other immune cell types (polymorphonuclear, eosinophils, basophils, mast cells, B-cells, NK cells), constitute the cellular component of the immune system. Under physiological conditions T cells function in immune surveillance and in the elimination of foreign antigen. However, under pathological conditions there is compelling evidence that T cells play a major role in the causation and propagation of disease. In these disorders, breakdown of T cell immunological tolerance, either central or peripheral is a fundamental process in the causation of autoimmune disease.
- T cells bind epitopes on small antigenic determinants on the surface of antigen- presenting cells that are associated with a major histocompatibility complex (MHC; in mice) or human leukocyte antigen (HLA; in humans) complex. T cells bind these epitopes through a T cell receptor (TCR) complex on the surface of the T cell.
- MHC major histocompatibility complex
- HLA human leukocyte antigen
- T cells bind these epitopes through a T cell receptor (TCR) complex on the surface of the T cell.
- TCR T cell receptor
- heterodimeric structures composed of two types of chains: an a (alpha) and b (beta) chain, or a Y (gamma) and d (delta) chain.
- the a chain is encoded by the nucleic acid sequence located within the a locus (on human or mouse chromosome 14), which also encompasses the entire d locus
- the b chain is encoded by the nucleic acid sequence located within the b locus (on mouse chromosome 6 or human chromosome 7).
- the majority of T cells have an ab TCR; while a minority of T cells bears a gd TCR.
- T cell receptor a and b polypeptides are linked to each other via a disulfide bond.
- Each of the two polypeptides that make up the TCR contains an extracellular domain comprising constant and variable regions, a
- the variable region of the TCR determines its antigen specificity, and similar to immunoglobulins, comprises three complementary determining regions (CDRs).
- the TCR is expressed on most T cells in the body and is known to be involved in the recognition of MHC-restricted antigens.
- the TCR a chain includes a covalently linked Va and Ca region, whereas the b chain includes a nb region covalently linked to a ⁇ b region.
- Va and nb regions form a pocket or cleft that can bind an antigen in the context of a major histocompatibility complex (MHC) (or HLA in humans).
- MHC major histocompatibility complex
- TCRs are detection molecules with tiny specificity, and exhibit, like antibodies, an enormous diversity.
- TCR molecules The general structure of TCR molecules and methods of making and using, including binding to a peptide:Major Histocompatibility Complex have been disclosed. See, for example PCT/US98/04274; PCT/US98/20263; W099/60120.
- Non-human animals e.g ., rodents, e.g., mice or rats
- rodents e.g., mice or rats
- TCR human or humanized T cell receptor
- variable domain encoded by at least one human TCR variable region gene segment
- mutagenesis a genetically modified mouse that allows for the production of fully human therapeutic TCRs against tumor and/or viral antigens, can be used to produce the TCRs of the invention.
- Those of skill in the art through standard mutagenesis techniques, in conjunction with the assays described herein, can obtain altered TCR sequences and test them for particular binding affinity and/or specificity.
- Useful mutagenesis techniques known in the art include, without limitation, de novo gene synthesis, oligonucleotide-directed mutagenesis, region-specific mutagenesis, linker-scanning mutagenesis, and site-directed mutagenesis by PCR (see, e.g., Sambrook et al. (1989) and Ausubel et al. (1999)).
- methods for generating a TCR to an NY-ESO-1 (157-165) peptide may include immunizing a non-human animal ⁇ e.g., a rodent, e.g., a mouse or a rat) , such as a genetically engineered non-human animal that comprises in its genome an un-rearranged human TCR variable gene locus, with an NY-ESO-1 (157-165) peptide; allowing the animal to mount an immune response to the peptide; isolating from the animal a T cell reactive to the peptide; determining a nucleic acid sequence of a human TCR variable region expressed by the T cell; cloning the human TCR variable region into a nucleotide construct comprising a nucleic acid sequence of a human TCR constant region such that the human TCR variable region is operably linked to the human TCR constant region; and expressing from the construct a human T cell receptor specific for the NY-ESO-1 (157-16).
- a rodent e.g.
- the steps of isolating a T cell, determining a nucleic acid sequence of a human TCR variable region expressed by the T cell, cloning the human TCR variable region into a nucleotide construct comprising a nucleic acid sequence of a human TCR constant region, and expressing a human T cell receptor are performed using standard techniques known to those of skill the art.
- the nucleotide sequence encoding a T cell receptor specific for an antigen of interest is expressed in a cell.
- the cell expressing the TCR is selected from a CHO, COS, 293, HeLa, PERC.6TM cell, etc.
- TCR-derived proteins may be modified by certain amino acid substitutions, additions, deletions, and post-translational modifications, without loss or reduction of biological activity.
- conservative amino acid substitutions that is, substitution of one amino acid for another amino acid of similar size, charge, polarity and conformation, are unlikely to significantly alter protein function.
- the 20 standard amino acids that are the constituents of proteins can be broadly categorized into four groups of conservative amino acids as follows: the nonpolar (hydrophobic) group includes alanine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan and valine; the polar (uncharged, neutral) group includes asparagine, cysteine, glutamine, glycine, serine, threonine and tyrosine; the positively charged (basic) group contains arginine, histidine and lysine; and the negatively charged (acidic) group contains aspartic acid and glutamic acid. Substitution in a protein of one amino acid for another within the same group is unlikely to have an adverse effect on the biological activity of the protein.
- a TCR of the present disclosure can comprise a CDR sequence (e.g., a CDR3 sequence such as a Va CDR3 or a nb CDR3) with 1 or more substitutions as compared to a CDR sequence (e.g., a CDR3 sequence such as a Va CDR3 or a nb CDR3) of Table 6.
- a TCR of the present disclosure can comprise a CDR sequence with 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more substitutions as compared to a CDR sequence of Table 6.
- the TCRs of the present invention function by binding to an HLA-A2 presented NY-ESO-1 (157-165) peptide.
- an HLA presented peptide can refer to a peptide that is bound to a human leukocyte antigen (HLA) protein, for example, an HLA protein expressed on the surface of a cell.
- HLA human leukocyte antigen
- a TCR that binds to an HLA presented peptide binds to the peptide that is bound by the HLA, and optionally also binds to the HLA itself. Interaction with the HLA can confer specificity for binding to a peptide presented by a particular HLA.
- the TCR binds to an isolated HLA presented peptide.
- the TCR binds to an HLA presented peptide on the surface of a cell.
- the TCRs of the present invention can function by binding to an HLA-A2 presented NY-ESO-1 (157-165) peptide.
- the present invention includes NY-ESO-1 TCRs that bind a NY-ESO-1 (157-165) peptide in the context of HLA-A2 with high specificity.
- the NY-ESO-1 TCRs do not bind to the NY-ESO-1 (157-165) peptide in the absence of HLA-A2, or such binding is minimal.
- the NY-ESO-1 TCRs do not bind to an off-target peptide in the context of HLA-A2, or such binding is minimal.
- an off-target peptide can refer to a peptide that differs from a target peptide by 1 , 2, 3, 4, 5, or more amino acids.
- binding specificity can be determined by a) measuring on-target binding (e.g., binding to the HLA-A2 presented NY-ESO-1 (157-165) peptide), b) measuring off-target binding, and c) quantifying the difference between the two, e.g., by calculating a ratio. This ratio can be calculated, for example, by dividing the values obtained in a) and b).
- Measurement of on-target and off-target binding can be achieved, for example, by measuring % binding to a peptide/HLA tetramer reagent (e.g., an NY-ESO- 1/HLA tetramer reagent or a MAGE-H1 90-98/HLA tetramer reagent), or by other techniques known in the art.
- a peptide/HLA tetramer reagent e.g., an NY-ESO- 1/HLA tetramer reagent or a MAGE-H1 90-98/HLA tetramer reagent
- an on-target binding/off-target binding value (e.g., a value obtained by dividing the values obtained in a) and b) described above) of a TCR of the present disclosure can be greater than 5, greater than 6, greater than 7, greater than 8, greater than 9, greater than 10, greater than 1 1 , greater than 12, greater than 13, greater than 14, greater than 15, greater than 16, greater than 17, greater than 18, greater than 19, greater than 20, greater than 21 , greater than 22, greater than 23, greater than 24, greater than 25, greater than 26, greater than 27, greater than 28, greater than 29, greater than 30, greater than 35, greater than 40, greater than 45, greater than 50, greater than 55, greater than 60, greater than 65, greater than 70, greater than 75, greater than 80, greater than 85, greater than 90, greater than 95, greater than 100, greater than 1 10, greater than 120, greater than 130, greater than 140, greater than 150, greater than 160, greater than 170, greater than 180, greater than 190, greater than 200, greater than 225, greater than 250, greater than 275, greater than 300, greater than
- an on-target binding/off-target binding value (e.g., a value obtained by dividing the values obtained in a) and b) described above) can be about 5 to about 20, about 10 to about 30, about 20 to about 80, about 30 to about 70, about 40 to about 60, about 50 to about 250, about 100 to about 200, about 100 to about 1000, about 300 to about 700, about 500 to about 1500, about 800 to about 1200, about 900 to about 1 100, about 800 to about 1500, about 1000 to about 1400, or about 1 100 to about 1300.
- the invention provides a recombinant antigen-binding protein (e.g., an isolated antigen-binding protein) that binds specifically to a conformational epitope of an HLA-A2 presented human NY-ESO-1 (157-165) peptide, wherein the antigen binding protein has a property selected from the group consisting of: (a) binds monomeric HLA-A2: NY-ESO-1 (157-165) peptide with a binding dissociation equilibrium constant (K D ) of less than about 20nM as measured in a surface plasmon resonance assay at 25°C; (b) binds monomeric HLA-A2:NY-ESO-1 (157-165) peptide with a binding dissociation equilibrium constant (K D ) of less than about 25nM as measured in a surface plasmon resonance assay at 25°C; (c) binds to HLA-A2:NY-ESO-1 (157-165 ) peptide-expressing cells with an
- the NY-ESO-1 TCRs of the present disclosure have specific activity or affinity for NY-ESO-1 (157-165) as measured by an in vitro assay.
- cells such as T2 cells
- expressing an HLA can be pulsed with a NY-ESO-1 (157-165) polypeptide, or an off-target polypeptide thereby inducing the cells to present the polypeptide bound to the HLA.
- an off-target HLA an HLA other than the HLA that is recognized by the TCR of interest
- an off-target HLA an HLA other than the HLA that is recognized by the TCR of interest
- an off-target HLA can be used to present the NY-ESO-1 peptide to test for specificity of binding to the HLA-A2-presented NY-ESO-1 1 peptide.
- a control can be a cell line that expresses neither NY-ESO-1 nor the target HLA (e.g., HLA- A2).
- Cells can be co-cultured with a T-cell population expressing the TCR of interest, and activity measured as a function of the amount of a cytokine (such as interferon gamma) produced by the cells.
- the assay can comprise in vitro co-cultures of a TCR-expresslng T cell population with 10 10 M peptide-ioaded T2 ceils at an effector celLtarget ceil ratio of 1 :1 (1 x 10 5 effector cells/96 well), and interferon gamma
- the assay can comprise in vitro co-cultures of a TCR- expressing T cell population and effector ceil at an effector celLtarget cell ratio of 5:1 (2.5 x 10 s effector celis:5 x 10 4 target cells), and interferon gamma measurement 24 hours after co- culture (e.g., by a Meso Scale Discovery (MSD®) Sector Imager).
- MSD® Meso Scale Discovery
- Increasing amounts of cytokine detected can serve as an indicator of activity.
- the activity or specificity of a TCR of interest to its target peptide in comparison to a control (off- target) polypeptide, or the activity or specificity of a TCR of interest to its on-target H LA- bound target peptide in comparison to an off-target HLA-bound target peptide can be 2-fold or greater, 3-fold or greater, 4-fold or greater, 5-fold or greater, 6-fold or greater, 7-fold or greater, 8-fold or greater, 9-fold or greater, 10-fold or greater, 15-fold or greater, 20-fold or greater, 30-fold or greater, 40-fold or greater, 50-fold or greater, 100 -fold or greater, 200-fold or greater, 300-fold or greater, 400-fold or greater, 500-foid or greater, 600-fold or greater, 700-fold or greater, 800-fold or greater, 900-fold or greater, 1 ,000-fold or greater, 1 ,500-fold or greater, 2,000-f
- the NY-ESO-1 TCRs of the present invention are useful in inhibiting the growth of a tumor or delaying the progression of cancer when administered prophylactically to a subject in need thereof and may increase survival of the subject.
- the administration of an NY-ESO-1 TCR of the present invention may lead to shrinking of a primary tumor and may prevent metastasis or development of secondary tumors.
- the NY-ESO-1 TCRs of the present invention are useful in inhibiting the growth of a tumor when administered therapeutically to a subject in need thereof and may increase survival of the subject.
- the administration of a therapeutically effective amount of an NY-ESO-1 TCR of the invention to a subject may lead to shrinking and disappearance of an established tumor in the subject.
- the invention provides an isolated TCR that specifically binds to an HLA-A2 presented NY-ESO-1 (157-165) peptide, wherein the antigen-binding protein exhibits one or more of the following characteristics: (i) comprises an alpha chain variable domain comprising complementary determining regions (CDR) 1 , CDR2, and CDR3, wherein the CDR3 region comprises the amino acid sequence of Formula I (SEQ ID NO: 1 18):
- N 2 is Leu, Tyr, Val, or Ala
- N 3 is Arg, Asn, Thr, or Ser
- N 4 is Pro, Ser, Glu, lie, Gly, Met, Lys, or Thr;
- N 5 which may or may not be present, is Lys
- N 6 which may or may not be present in Asp, Ala, Gly, Leu, or Asn;
- N 7 is Ser, Asn, Ala, Tyr, or Thr;
- N 8 which may or may not be present, is Ser or Gly
- N g which may or may not be present, is Gly
- N 10 which may or may not be present, is Gly or Ser;
- N which may or may not be present, is Trp, Gly, Ser, Gin, Ala, or Pro;
- N 12 is Gly, Tyr, Asn, Gin, or Ser;
- N 13 is Lys, Ala, Asp, lie, or Asn;
- N 14 is a nonpolar amino acid
- N 15 is Gin, Asn, Arg, Thr, Val, lie, or Ser; optionally wherein Ni is Ala or lie; and/or wherein N 14 is Phe, Leu, Met, or Pro; (ii) comprises a beta chain variable domain comprising beta chain variable domain comprises complementary determining regions (CDR) 1 , CDR2, and CDR3, wherein the CDR3 region comprises amino acid sequence of Formula II (SEQ ID NO: 1 19):
- Ni and N 2 are each independently Ala or Ser;
- N 3 is Ser, Met, or Lys
- N 4 is Tyr, Trp, His, Leu, Thr, Glu or Gin;
- N 5 is Ser, Ala, Thr, Gly, Val, or Arg;
- N 6 which may or may not be present, is Gly, His, Asp, Thr, Pro, Met, or Ser;
- N 7 which may or may not be present, is Gly, Tyr, Asn, or Pro;
- N 8 which may or may not be present, is Y;
- N g which may or may not be present, is N;
- N 10 which may or may not be present, is a polar amino acid;
- N is Pro, Glu, Gly, or Asp
- N 12 which may or may not be present, is Glu
- N 13 is Leu, Ala, Gin, or Tyr;
- N 14 is His, Phe, or Thr; optionally wherein N 10 is Ser, Thr, Gin, or Tyr; (iii) comprises a CDR1 of the alpha chain variable domain comprising any one of the CDR1 amino acid sequences set forth in Table 1 , or a substantially similar sequence thereof having at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity, and a CDR2 of the alpha chain variable domain independently comprising any one of the CDR2 amino acid sequences set forth in Table 1 , or a substantially similar sequence thereof having at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; (iv) comprises a CDR1 of a beta chain variable domain comprising any one of the CDR1 amino acid sequences set forth in Table 1 , or a substantially similar sequence thereof having at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least
- (x) comprises an alpha chain variable domain/beta chain variable domain amino acid sequence pair selected from the group consisting of SEQ ID NOs: 9/7; 19/17; 29/27; 39/37; 49/47; 59;57; 69/67; 79/77; 89/87; 99/97; and 109/107, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity; (xi) does not specifically bind to cells expressing predicted off-target peptides but not an HLA-A2 presented NY-ESO-1 peptide comprising the amino acid sequence of SEQ ID NO: 1 1 1 , as determined by luminescence assay; and
- the TCRs of the present invention may possess one or more of the aforementioned biological characteristics, or any combinations thereof.
- Other biological characteristics of the antigen-binding proteins of the present invention will be evident to a person of ordinary skill in the art from a review of the present disclosure including the working Examples herein.
- a polynucleotide encoding an NY-ESO-1 TCR described herein is inserted into a vector.
- vector refers to a vehicle into which a polynucleotide encoding a protein may be covalently inserted so as to bring about the expression of that protein and/or the cloning of the polynucleotide.
- vectors may also be referred to as "expression vectors".
- the isolated polynucleotide may be inserted into a vector using any suitable methods known in the art, for example, without limitation, the vector may be digested using appropriate restriction enzymes and then may be ligated with the isolated polynucleotide having matching restriction ends.
- Expression vectors have the ability to incorporate and express heterologous or modified nucleic acid sequences coding for at least part of a gene product capable of being transcribed in a cell. In most cases, RNA molecules are then translated into a protein. Expression vectors can contain a variety of control sequences, which refer to nucleic acid sequences necessary for the transcription and possibly translation of an operatively linked coding sequence in a particular host organism.
- vectors and expression vectors may contain nucleic acid sequences that serve other functions as well and are discussed infra.
- An expression vector may comprise additional elements, for example, the expression vector may have two replication systems, thus allowing it to be maintained in two organisms, for example in human cells for expression and in a prokaryotic host for cloning and amplification.
- the expression vector may have the necessary 5' upstream and 3' downstream regulatory elements such as promoter sequences such as CMV, PGK and EF1 a promoters, ribosome recognition and binding TATA box, and 3' UTR AAUAAA transcription termination sequence for the efficient gene transcription and translation in its respective host cell.
- promoter sequences such as CMV, PGK and EF1 a promoters
- ribosome recognition and binding TATA box such as ribosome recognition and binding TATA box, and 3' UTR AAUAAA transcription termination sequence for the efficient gene transcription and translation in its respective host cell.
- Other suitable promoters include the constitutive promoter of simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), HIV LTR promoter, MoMuLV promoter, avian leukemia virus promoter, EBV immediate early promoter, and rous sarcoma virus promoter.
- Human gene promoters may also be used, including, but not limited to the actin promoter, the myosin promoter, the hemoglobin promoter, and the creatine kinase promoter.
- inducible promoters are also contemplated as part of the vectors expressing chimeric antigen receptor. This provides a molecular switch capable of turning on expression of the polynucleotide sequence of interest or turning off expression. Examples of inducible promoters include, but are not limited to a metallothionine promoter, a
- the expression vector may have additional sequence such as 6x-histidine (SEQ ID NO: 165), c-Myc, and FLAG tags which are incorporated into the expressed TCRs.
- the expression vector may be engineered to contain 5' and 3' untranslated regulatory sequences that sometimes can function as enhancer sequences, promoter regions and/or terminator sequences that can facilitate or enhance efficient transcription of the nucleic acid(s) of interest carried on the expression vector.
- An expression vector may also be engineered for replication and/or expression functionality (e.g ., transcription and translation) in a particular cell type, cell location, or tissue type. Expression vectors may include a selectable marker for maintenance of the vector in the host or recipient cell.
- vectors are plasmid, autonomously replicating sequences, and transposable elements.
- Additional exemplary vectors include, without limitation, plasmids, phagemids, cosmids, artificial chromosomes such as yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC), or P1 -derived artificial chromosome (PAC), bacteriophages such as lambda phage or M13 phage, and animal viruses.
- Examples of categories of animal viruses useful as vectors include, without limitation, retrovirus (including lentivirus), adenovirus, adeno-associated virus, herpesvirus ⁇ e.g., herpes simplex virus), poxvirus, baculovirus, papillomavirus, and papovavirus ⁇ e.g., SV40).
- retrovirus including lentivirus
- adenovirus adeno-associated virus
- herpesvirus ⁇ e.g., herpes simplex virus
- poxvirus baculovirus
- papillomavirus papillomavirus
- papovavirus ⁇ e.g., SV40
- expression vectors are Lenti-XTM Bicistronic Expression System (Neo) vectors (Clontrch), pCIneo vectors (Promega) for expression in mammalian cells; pLenti4/V5-DEST.TM., pLenti6/V5- DEST.TM., and pLenti6.2N5-GW/lacZ (Invitrogen) for lentivirus-mediated gene transfer and expression in mammalian cells.
- the coding sequences of the TCRs disclosed herein can be ligated into such expression vectors for the expression of the chimeric protein in mammalian cells.
- the nucleic acids encoding the TCR of the present invention are provided in a viral vector.
- a viral vector can be those derived from retrovirus, lentivirus, or foamy virus.
- viral vector refers to a nucleic acid vector construct that includes at least one element of viral origin and has the capacity to be packaged into a viral vector particle.
- the viral vector can contain the coding sequence for the various proteins described herein in place of nonessential viral genes.
- the vector and/or particle can be utilized for the purpose of transferring DNA, RNA or other nucleic acids into cells either in vitro or in vivo. Numerous forms of viral vectors are known in the art.
- the viral vector containing the coding sequence for a TCR described herein is a retroviral vector or a lentiviral vector.
- retroviral vector refers to a vector containing structural and functional genetic elements that are primarily derived from a retrovirus.
- lentiviral vector refers to a vector containing structural and functional genetic elements outside the LTRs that are primarily derived from a lentivirus.
- the retroviral vectors for use herein can be derived from any known retrovirus (e.g ., type c retroviruses, such as Moloney murine sarcoma virus (MoMSV), Harvey murine sarcoma virus (HaMuSV), murine mammary tumor virus (MuMTV), gibbon ape leukemia virus (GaLV), feline leukemia virus (FLV), spumavirus, Friend, Murine Stem Cell Virus (MSCV) and Rous Sarcoma Virus (RSV)).
- type c retroviruses such as Moloney murine sarcoma virus (MoMSV), Harvey murine sarcoma virus (HaMuSV), murine mammary tumor virus (MuMTV), gibbon ape leukemia virus (GaLV), feline leukemia virus (FLV), spumavirus, Friend, Murine Stem Cell Virus (MSCV) and Rous Sarcoma Virus (RSV)).
- Retroviruses also include human T cell leukemia viruses, HTLV-1 and HTLV-2, and the lentiviral family of retroviruses, such as Human Immunodeficiency Viruses, HIV-1 , HIV-2, simian immunodeficiency virus (SIV), feline immunodeficiency virus (FIV), equine immnodeficiency virus (EIV), and other classes of retroviruses.
- retroviruses such as Human Immunodeficiency Viruses, HIV-1 , HIV-2, simian immunodeficiency virus (SIV), feline immunodeficiency virus (FIV), equine immnodeficiency virus (EIV), and other classes of retroviruses.
- a lentiviral vector for use herein refers to a vector derived from a lentivirus, a group (or genus) of retroviruses that give rise to slowly developing disease.
- Viruses included within this group include HIV (human immunodeficiency virus; including HIV type 1 , and HIV type 2); visna-maedi; a caprine arthritis-encephalitis virus; equine infectious anemia virus; feline immunodeficiency virus (FIV); bovine immune deficiency virus (BIV); and simian
- Retroviral vectors for use in the present invention can be formed using standard cloning techniques by combining the desired DNA sequences in the order and orientation described herein (Current Protocols in Molecular Biology, Ausubel, F. M. et al. (eds.) Greene Publishing Associates, (1989), Sections 9.10- 9.14 and other standard laboratory manuals; Eglitis, et al. (1985) Science 230:1395-1398; Danos and Mulligan (1988) Proc. Natl. Acad. Sci. USA 85:6460-6464; Wilson et al. (1988) Proc. Natl. Acad. Sci.
- Suitable sources for obtaining retroviral (i.e., both lentiviral and non-lentiviral) sequences for use in forming the vectors include, for example, genomic RNA and cDNAs available from commercially available sources, including the Type Culture Collection
- the vector may be introduced into a host cell to allow expression of the polypeptide within the host cell.
- the expression vectors may contain a variety of elements for controlling expression, including without limitation, promoter sequences, transcription initiation sequences, enhancer sequences, selectable markers, and signal sequences. These elements may be selected as appropriate by a person of ordinary skill in the art, as described above.
- the promoter sequences may be selected to promote the transcription of the polynucleotide in the vector. Suitable promoter sequences include, without limitation, T7 promoter, T3 promoter, SP6 promoter, beta-actin promoter,
- Enhancer sequences may be selected to enhance the transcription of the polynucleotide.
- Selectable markers may be selected to allow selection of the host cells inserted with the vector from those not, for example, the selectable markers may be genes that confer antibiotic resistance. Signal sequences may be selected to allow the expressed polypeptide to be transported outside of the host cell.
- the vector may be introduced into a host cell (an isolated host cell) to allow replication of the vector itself and thereby amplify the copies of the polynucleotide contained therein.
- the cloning vectors may contain sequence components generally include, without limitation, an origin of replication, promoter sequences, transcription initiation sequences, enhancer sequences, and selectable markers. These elements may be selected as appropriate by a person of ordinary skill in the art.
- the origin of replication may be selected to promote autonomous replication of the vector in the host cell.
- the present disclosure provides isolated host cells containing the vectors provided herein.
- the host cells containing the vector may be useful in expression or cloning of the polynucleotide contained in the vector.
- Suitable host cells can include, without limitation, prokaryotic cells, fungal cells, yeast cells, or higher eukaryotic cells such as mammalian cells.
- Suitable prokaryotic cells for this purpose include, without limitation, eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as Escherichia, e.g., E.
- the TCRs of the present invention are introduced into a host cell using transfection and/or transduction techniques known in the art.
- transfection and/or transduction
- the terms, "transfection,” and, “transduction,” refer to the processes by which an exogenous nucleic acid sequence is introduced into a host cell.
- the nucleic acid may be integrated into the host cell DNA or may be maintained extrachromosomally.
- the nucleic acid may be maintained transiently or a may be a stable introduction.
- Transfection may be accomplished by a variety of means known in the art including but not limited to calcium phosphate-DNA co-precipitation, DEAE-dextran- mediated transfection, polybrene-mediated transfection, electroporation, microinjection, liposome fusion, lipofection, protoplast fusion, retroviral infection, and biolistics.
- Transduction refers to the delivery of a gene(s) using a viral or retroviral vector by means of viral infection rather than by transfection.
- retroviral vectors are transduced by packaging the vectors into virions prior to contact with a cell.
- a nucleic acid encoding an NY-ESO-1 TCR of the invention carried by a retroviral vector can be transduced into a cell through infection and pro virus integration.
- the term “genetically engineered” or “genetically modified” refers to the addition of extra genetic material in the form of DNA or RNA into the total genetic material in a cell.
- the terms, “genetically modified cells,” “modified cells,” and, “redirected cells,” are used interchangeably.
- the TCRs of the present invention are introduced and expressed in immune effector cells so as to redirect their specificity to a target antigen of interest, e.g., a an HLA-A2 displayed NY-ESO-1 peptide, e.g., amino acid residues 157-165.
- a target antigen of interest e.g., a an HLA-A2 displayed NY-ESO-1 peptide, e.g., amino acid residues 157-165.
- the present invention provides methods for making the immune effector cells which express the TCRs as described herein.
- the method comprises transfecting or transducing immune effector cells, e.g., immune effector cells isolated from a subject, such as a subject having an NY-ESO-1 -associated disease or disorder, such that the immune effector cells express one or more TCR as described herein.
- the immune effector cells are isolated from an individual and genetically modified without further manipulation in vitro. Such cells can then be directly re-administered into the individual.
- the immune effector cells are first activated and stimulated to proliferate in vitro prior to being genetically modified to express a TCR.
- the immune effector cells may be cultured before or after being genetically modified (/.e., transduced or transfected to express a TCR as described herein).
- the source of cells may be obtained from a subject.
- the immune effector cells for use with the TCRs as described herein comprise T cells.
- T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph nodes tissue, cord blood, thymus issue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors.
- sources including peripheral blood mononuclear cells, bone marrow, lymph nodes tissue, cord blood, thymus issue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors.
- T cell can be obtained from a unit of blood collected from the subject using any number of techniques known to the skilled person, such as FICOLL separation.
- cells from the circulating blood of an individual are obtained by apheresis.
- the apheresis product typically contains lymphocytes, including T cells, monocytes, granulocyte, B cells, other nucleated white blood cells, red blood cells, and platelets.
- the cells collected by apheresis may be washed to remove the plasma fraction and to place the cells in an appropriate buffer or media for subsequent processing.
- the cells are washed with PBS.
- the washed solution lacks calcium and may lack magnesium or may lack many if not all divalent cations.
- a washing step may be accomplished by methods known to those in the art, such as by using a semiautomated flow-through centrifuge. After washing, the cells may be resuspended in a variety of biocompatible buffers or other saline solution with or without buffer. In certain embodiments, the undesirable components of the apheresis sample may be removed in the cell directly resuspended culture media.
- T cells are isolated from peripheral blood mononuclear cells (PBMCs) by lysing the red blood cells and depleting the monocytes, for example, by centrifugation through a PERCOLLTM gradient.
- PBMCs peripheral blood mononuclear cells
- a specific subpopulation of T cells such as CD28+, CD4+, CD8+, CD45RA+, and CD45RO+ T cells, can be further isolated by positive or negative selection techniques.
- enrichment of a T cell population by negative selection can be accomplished with a combination of antibodies directed to surface markers unique to the negatively selected cells.
- One method for use herein is cell sorting and/or selection via negative magnetic immunoadherence or flow cytometry that uses a cocktail of monoclonal antibodies directed to cell surface markers present on the cells negatively selected.
- a monoclonal antibody cocktail typically includes antibodies to CD14, CD20, CD1 1 b, CD16, HLA-DR, and CD8.
- Flow cytometry and cell sorting may also be used to isolate cell populations of interest for use in the present invention.
- PBMC may be used directly for genetic modification with the TCRs using methods as described herein.
- T lymphocytes after isolation of PBMC, T lymphocytes are further isolated and in certain embodiments, both cytotoxic and helper T lymphocytes can be sorted into naive, memory, and effector T cell subpopulations either before or after genetic modification and/or expansion.
- the immune effector cells can be genetically modified following isolation using known methods, or the immune effector cells can be activated and expanded (or differentiated in the case of progenitors) in vitro prior to being genetically modified.
- the immune effector cells such as T cells
- Methods for activating and expanding T cells are known in the art and are described, for example, in U.S. Pat. No. 6,905,874; U.S. Pat. No. 6,867,041 ; U.S.
- the invention provides a population of modified immune effector cells for the treatment of an NY-ESO-1 -associated disease or disorder, e.g., cancer, the modified immune effector cells comprising an NY-ESO-1 TCR as disclosed herein.
- TCR-expressing immune effector cells prepared as described herein can be utilized in methods and compositions for adoptive immunotherapy in accordance with known techniques, or variations thereof that will be apparent to those skilled in the art based on the instant disclosure. See, e.g., US Patent Application Publication No. 2003/0170238 to Gruenberg et al; see also U.S. Pat. No. 4,690,915 to Rosenberg.
- the invention provides therapeutic compositions comprising the NY-ESO-1 TCRs of the invention or immune effector cells comprising the NY-ESO-1 TCRs of the invention.
- Therapeutic compositions in accordance with the invention will be administered with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like.
- suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like.
- a multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's
- compositions include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTINTM), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax
- the frequency and the duration of the treatment can be adjusted.
- the initial dose may be followed by administration of a second or a plurality of subsequent doses of NY-ESO-1 TCRs of the invention or immune effector cells comprising the NY-ESO-1 TCRs of the invention in an amount that can be approximately the same or less than that of the initial dose.
- the pharmaceutical composition can be delivered in a controlled release system.
- a pump may be used.
- the injectable preparations may include dosage forms for intravenous,
- injectable preparations may be prepared by methods publicly known.
- the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antigen-binding protein or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections.
- aqueous medium for injections there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g ., ethanol), a polyalcohol (e.g ., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc.
- an alcohol e.g ethanol
- a polyalcohol e.g ., propylene glycol, polyethylene glycol
- a nonionic surfactant e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)
- oily medium there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.
- a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.
- TCR-expressing immune effector cells are formulated by first harvesting them from their culture medium, and then washing and concentrating the cells in a medium and container system suitable for administration (a "pharmaceutically acceptable" carrier) in a treatment-effective amount.
- a medium and container system suitable for administration a "pharmaceutically acceptable” carrier
- Suitable infusion medium can be any isotonic medium formulation, typically normal saline, Normosol R (Abbott) or Plasma-Lyte A (Baxter), but also 5% dextrose in water or Ringer's lactate can be utilized.
- the infusion medium can be supplemented with human serum albumin.
- a treatment-effective amount of cells in the composition is typically greater than 10 2 cells, and up to 10 6 up to and including 10 8 or 10 9 cells and can be more than 10 10 cells.
- the number of cells will depend upon the ultimate use for which the composition is intended as will the type of cells included therein.
- the cells may be autologous or heterologous to the patient undergoing therapy.
- the treatment may also include administration of mitogens ⁇ e.g., PHA) or lymphokines, cytokines, and/or chemokines ⁇ e.g., IFN-g, IL-2, IL-12, TNF-a, IL-18, and TNF- b, GM-CSF, IL-4, IL-13, Flt3-L, RANTES, MIP1 a, etc.) as described herein to enhance induction of the immune response.
- mitogens ⁇ e.g., PHA
- lymphokines e.g., cytokines, and/or chemokines ⁇ e.g., IFN-g, IL-2, IL-12, TNF-a, IL-18, and TNF- b, GM-CSF, IL-4, IL-13, Flt3-L, RANTES, MIP1 a, etc.
- compositions of the present invention may be administered either alone, or as a pharmaceutical composition in combination with diluents and/or with other components such as IL-2 or other cytokines or cell populations.
- pharmaceutical compositions of the present invention may comprise a TCR- expressing immune effector cell population, such as T cells, as described herein, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients.
- Such compositions may comprise buffers such as neutral buffered saline, phosphate buffered saline and the like; carbohydrates such as glucose, mannose, sucrose or dextrans, mannitol; proteins; polypeptides or amino acids such as glycine;
- compositions of the present invention are preferably formulated for intravenous administration.
- the anti-tumor immune response induced in a subject by administering TCR expressing T cells described herein using the methods described herein, or other methods known in the art may include cellular immune responses mediated by cytotoxic T cells capable of killing infected cells, regulatory T cells, and helper T cell responses.
- Humoral immune responses mediated primarily by helper T cells capable of activating B cells thus leading to antibody production, may also be induced.
- a variety of techniques may be used for analyzing the type of immune responses induced by the compositions of the present invention, which are well described in the art; e.g., Current Protocols in Immunology, Edited by: John E. Coligan, Ada M. Kruisbeek, David H. Margulies, Ethan M. Shevach, Warren Strober (2001 ) John Wiley & Sons, NY, N.Y.
- the NY-ESO-1 TCRs of the invention are useful, inter alia, for the treatment, prevention and/or amelioration of any disease or disorder associated with or mediated by NY-ESO-1 .
- the present invention provides methods for treating an NY-ESO-1 - associated disease or disorder, such as an NY-ESO-1 -associated cancer (e.g., an NY-ESO- 1 -positive cancer) (tumor growth inhibition) by administering an NY-ESO-1 TCR (or pharmaceutical composition comprising an NY-ESO-1 TCR or a plurality of cells comprising an NY-ESO-1 TCR) as described herein to a patient in need of such treatment, and NY- ESO-1 TCRs (or pharmaceutical composition comprising an NY-ESO-1 TCR) for use in the treatment of an NY-ESO-1 -associated cancer.
- an NY-ESO-1 -associated cancer e.g., an NY-ESO- 1 -positive cancer
- NY- ESO-1 TCRs or pharmaceutical composition comprising an NY-ESO-1
- the antigen-binding proteins of the present invention are useful for the treatment, prevention, and/or amelioration of disease or disorder or condition such as an NY-ESO-1 -associated cancer and/or for ameliorating at least one symptom associated with such disease, disorder or condition.
- disease or disorder or condition such as an NY-ESO-1 -associated cancer
- the NY-ESO-1 TCR or pharmaceutical composition or plurality of cells
- the present invention provides for methods of treating an individual diagnosed with or suspected of having, or at risk of developing, an NY-ESO-1 -associated disease or disorder, e.g., an NY-ESO-1 -associated cancer, comprising administering the individual a therapeutically effective amount of the TCR-expressing immune effector cells as described herein.
- an NY-ESO-1 -associated disease or disorder e.g., an NY-ESO-1 -associated cancer
- the invention provides a method of treating a subject diagnosed with an NY-ESO-1 -positive cancer comprising removing immune effector cells from a subject diagnosed with an NY-ESO-1 -positive cancer, genetically modifying said immune effector cells with a vector comprising a nucleic acid encoding a TCR of the instant invention, thereby producing a population of modified immune effector cells, and administering the population of modified immune effector cells to the same subject.
- the immune effector cells comprise T cells.
- the methods for administering the cell compositions described herein includes any method which is effective to result in reintroduction of ex vivo genetically modified immune effector cells that either directly express a TCR of the invention in the subject or on reintroduction of the genetically modified progenitors of immune effector cells that on introduction into a subject differentiate into mature immune effector cells that express the TCR.
- One method comprises transducing peripheral blood T cells ex vivo with a nucleic acid construct in accordance with the invention and returning the transduced cells into the subject.
- compositions described herein are useful for treating subjects suffering from primary or recurrent cancer, including, but not limited to, NY-ESO-1 -associated cancer, e.g., NY-ESO-1 -associated cancer is a
- liposarcoma a neuroblastoma, a myeloma, a metastatic melanoma, a synovial sarcoma, a bladder cancer, an esophageal cancer, a hepatocellular cancer, a head and neck cancer, a non-small cell lung cancer, an ovarian cancer, a prostate cancer, a breast cancer, astrocytic tumor, glioblastoma multiforme, anaplastic astrocytoma, brain tumor, fallopian tube cancer, ovarian epithelial cancer, primary peritoneal cavity cancer, advanced solid tumors, soft tissue sarcoma, melanoma, a sarcoma, myelodysplastic syndrome, acute myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, Hodgkin disease, multiple myeloma, synovial sarcoma, metastatic solid tumors, esophageal cancer,
- the NY-ESO-1 -associated cancer is a liposarcoma, a neuroblastoma, a myeloma, a metastatic melanoma, a synovial sarcoma, a bladder cancer, an esophageal cancer, a hepatocellular cancer, a head and neck cancer, a non-small cell lung cancer, an ovarian cancer, a prostate cancer, or a breast cancer.
- the TCRs may be used to treat early stage or late-stage symptoms of the NY-ESO- 1 -associated cancer.
- a TCR of the invention may be used to treat advanced or metastatic cancer.
- the TCRs are useful in reducing or inhibiting or shrinking tumor growth.
- treatment with aa TCR of the invention leads to more than 40% regression, more than 50% regression, more than 60% regression, more than 70% regression, more than 80% regression or more than 90% regression of a tumor in a subject.
- the TCRs may be used to prevent relapse of a tumor.
- the TCRs are useful in extending progression-free survival or overall survival in a subject with NY-ESO-1 -associated cancer.
- the TCRs are useful in reducing toxicity due to chemotherapy or radiotherapy while maintaining long- term survival in a patient suffering from NY-ESO-1 -associated cancer.
- One or more TCRs of the present invention may be administered to relieve or prevent or decrease the severity of one or more of the symptoms or conditions of the disease or disorder.
- TCRs of the present invention prophylactically to patients at risk for developing a disease or disorder such as NY-ESO-1 - associated disease or disorder, such as an NY-ESO-1 -associated cancer.
- the present TCRs are used for the preparation of a pharmaceutical composition for treating patients suffering from NY-ESO-1 - associated disease or disorder, such as an NY-ESO-1 -associated cancer.
- the present TCRs are used as adjunct therapy with any other agent or any other therapy known to those skilled in the art useful for treating NY-ESO-1 - associated cancer.
- Combination therapies may include an NY-ESO-1 TCR of the invention, such as immune effector cell comprising a TCR of the invention, or a pharmaceutical composition of the invention, and any additional therapeutic agent that may be advantageously combined with a TCR of the invention.
- the TCRs of the present invention may be combined synergistically with one or more anti-cancer drugs or therapy used to treat or inhibit an NY- ESO-1 -associated disease or disorder, such as NY-ESO-1 -positive cancer, e.g., a liposarcoma, a neuroblastoma, a myeloma, a metastatic melanoma, a synovial sarcoma, a bladder cancer, an esophageal cancer, a hepatocellular cancer, a head and neck cancer, a non-small cell lung cancer, an ovarian cancer, a prostate cancer, a breast cancer, astrocytic tumor, glioblastoma multiforme, anaplastic astrocytoma, brain tumor, fallopian tube cancer, ovarian epithelial cancer, primary peritoneal cavity cancer, advanced solid tumors, soft tissue sarcoma, melanoma, a sarcoma, myelodysplastic syndrome,
- the immunostimulatory therapies include direct immunostimulatory therapies to augment immune cell activity by either“releasing the brake” on suppressed immune cells or“stepping on the gas” to activate an immune response. Examples include targeting other checkpoint receptors, vaccination and adjuvants.
- the immunosupportive modalities may increase antigenicity of the tumor by promoting immunogenic cell death, inflammation or have other indirect effects that promote an anti- tumor immune response. Examples include radiation, chemotherapy, anti-angiogenic agents, and surgery.
- one or more TCRs of the present invention may be used in combination with a PD-1 inhibitor (e.g ., an anti-PD-1 antibody such as nivolumab, pembrolizumab, pidilizumab, BGB-A317 or REGN2810), a PD-L1 inhibitor ⁇ e.g., an anti-PD- L1 antibody such as avelumab, atezolizumab, durvalumab, MDX-1 105, or REGN3504 ), a CTLA-4 inhibitor ⁇ e.g., ipilimumab), a TIM3 inhibitor, a BTLA inhibitor, a TIGIT inhibitor, a CD47 inhibitor, a GITR inhibitor, an antagonist of another T cell co-inhibitor or ligand ⁇ e.g., an antibody to CD-28, 2B4, LY108, LAIR1 , ICOS, CD160 or VISTA), an indoleamine
- a PD-1 inhibitor
- VEGF receptor ⁇ e.g., sunitinib, sorafenib, or pazopanib
- an Ang2 inhibitor ⁇ e.g., nesvacumab
- T ⁇ Rb transforming growth factor beta
- EGFR epidermal growth factor receptor
- a CD20 inhibitor ⁇ e.g., an anti-CD20 antibody such as rituximab
- an antibody to a tumor-specific antigen e.g., CA9, CA125, melanoma-associated antigen 3 (MAGE3), carcinoembryonic antigen (CEA), vimentin, tumor-M2-PK, prostate-specific antigen (PSA), mucin-1 , MART-1 , and CA19-9
- a vaccine ⁇ e.g., Bacillus Calmette
- Examples of cancer vaccines that can be used in combination with TCRs of the present invention include MAGE3 vaccine for melanoma and bladder cancer, MUC1 vaccine for breast cancer, EGFRv3 ⁇ e.g., Rindopepimut) for brain cancer (including glioblastoma multiforme), or ALVAC-CEA (for CEA+ cancers).
- the NY-ESO-1 TCRs of the invention may be administered in combination with radiation therapy in methods to generate long-term durable anti-tumor responses and/or enhance survival of patients with cancer.
- the NY- ESO-1 TCRs of the invention may be administered prior to, concomitantly or after administering radiation therapy to a cancer patient.
- radiation therapy may be administered in one or more doses to tumor lesions followed by administration of one or more doses of NY-ESO-1 TCRs of the invention.
- radiation therapy may be administered locally to a tumor lesion to enhance the local immunogenicity of a patient’s tumor (adjuvinating radiation) and/or to kill tumor cells (ablative radiation) followed by systemic administration of an NY-ESO-1 TCRs of the invention.
- the additional therapeutically active agent(s)/component(s) may be administered prior to, concurrent with, or after the administration of the NY-ESO-1 TCRs of the present invention.
- administration regimens are considered the administration of an NY-ESO-1 TCR“in combination with” a second therapeutically active component.
- the additional therapeutically active component(s) may be administered to a subject prior to administration of an NY-ESO-1 TCR of the present invention. In other embodiments, the additional therapeutically active component(s) may be administered to a subject after administration of an NY-ESO-1 TCR of the present invention. In yet other embodiments, the additional therapeutically active component(s) may be administered to a subject concurrent with administration of an NY-ESO-1 TCR of the present invention.
- Constant administration for purposes of the present invention, includes, e.g., administration of an NY-ESO-1 TCR and an additional therapeutically active component to a subject in a single dosage form (e.g., co-formulated), or in separate dosage forms administered to the subject within about 30 minutes or less of each other. If administered in separate dosage forms, each dosage form may be administered via the same route;
- each dosage form may be administered via a different route.
- administering the components in a single dosage from, in separate dosage forms by the same route, or in separate dosage forms by different routes are all considered “concurrent administration," for purposes of the present disclosure.
- administration of an NY-ESO-1 TCR "prior to”, “concurrent with,” or “after” (as those terms are defined herein above) administration of an additional therapeutically active component is considered administration of an NY-ESO-1 TCR "in combination with” an additional therapeutically active component).
- mice humanized for cellular immune system components, VelociTTM mice (see, e.g., PCT Publication No. WO 2016/164492, the entire contents of which are incorporated herein by reference), were immunized with NY-ESO-1 (157-165) peptide (SLLMWITQC,
- SEQ ID NO: 1 1 1 presented specifically by human HLA-A2, diluted in PBS and mixed with adjuvant, e.g. in equal volume with Complete Freund's Adjuvant (CFA; Chondrex, Inc.).
- CFA Complete Freund's Adjuvant
- Spleen suspensions from immunized mice were obtained and dissociated. Red blood cells were lysed in ACK lysis buffer (Life Technologies), and splenocytes were suspended in RPMI complete media. Isolated splenocytes were sorted and single T cells that bind NY- ESO-1 (157-165) peptide in the context of MHC were isolated by fluorescent-activated cell sorting (FACS). Isolated T cells were single well plated and mixed with TCR alpha and beta variable region-specific PCR primers.
- cDNAs for each single T cell were synthesized via a reverse transcriptase (RT) reaction. Each resulting RT product was then split and transferred into two corresponding wells for subsequent TCR beta and alpha PCRs.
- One set of the resulting RT products was first amplified by PCR using a 5’ degenerate primer specific for TCR beta variable region leader sequence or a 5’ degenerate primer specific for TCR alpha chain variable region leader sequence and a 3’ primer specific for TCR constant region, to form an amplicon.
- the amplicons were then amplified again by PCR using a 5’ degenerate primer specific for TCR beta variable region framework 1 or a 5’ degenerate primer specific for TCR alpha chain variable region framework 1 and a 3’ primer specific for TCR constant region, to generate amplicons for cloning.
- the TCR beta and alpha derived PCR products were cloned into expression vectors containing beta constant region and alpha constant region, respectively.
- the expression vectors expressing full-length beta and alpha chain pairs were cloned into CHO cells and tested for binding specificity to commercial NY-ESO- 1/HLA tetramer reagents (HLA-A02:01 NY-ESO-1 tetramer; MBL International Corporation).
- Table 1 provides a detailed list of the alpha and beta chain CDR1 , CDR2, and CDR3 amino acid sequences of the TCRs that were isolated
- Table 2 provides the corresponding polynucleic acid sequences
- Table 3 provides the amino acid and nucleotide sequences of the alpha and beta chain variable regions of the isolated TCRs.
- the VelociTTM TCRs were cloned from CD8-positive VelociTTM mouse T cells, the TCRs were expressed in CHO cells in the absence of any CD8, and still demonstrated binding the NY-ESO peptide tetramer. Without being bound by any theory, the VelociTTM derived TCRs may bind to T cells in the absence of CD8, for example double negative (CD4-CD8-) T cells.
- Table 3 Amino acid and nucleic sequences for VelociTTM TCRs specific for NY-ESO-1 (157-165) / HLA-A2
- Example 2 Reporter T cell/APC luciferase assay to measure and assess T cell receptor specific activity
- T cell activation is achieved by stimulating T cell receptors (TCRs) that recognize specific peptides presented by major histocompatibility complex class I or II proteins on antigen- presenting cells (APC).
- TCRs T cell receptors
- APC antigen- presenting cells
- Activated TCRs in turn initiate a cascade of signaling events that can be monitored by reporter genes driven by transcription factors such as activator-protein 1 (AP-1 ), Nuclear Factor of Activated T cells (NFAT) or Nuclear factor kappa-light-chain-enhancer of activated B cells (NFicb).
- AP-1 activator-protein 1
- NFAT Nuclear Factor of Activated T cells
- NFicb Nuclear factor kappa-light-chain-enhancer of activated B cells
- a bioassay was developed to measure TCR mediated T cell signaling induced by interaction between WT human HLA-A2/NY-ESO-1 (157-165) specific TCRs and HLA-A2+ APCs presenting the NY-ESO-1 peptide.
- Jurkat clone J.RT3.T3.5 (ATCC #TIB-153) which lacks its own endogenous TCR was transduced by lentiviruses encoding the human CD8A/B genes, Cignal Lenti AP-1 Luciferase Reporter (Qiagen - SAbiosciences, #CLS-01 1 L) and NY- ESO-1 specific TCRs derived either from immunization of VelociTTM mice (WO 2016/164492) or from published comparator NY-ESO-1 TCRs (1 G4 and clone 1 13: Li, Y. et al. Nat Biotechnol 2005;23:349-354).
- RPMI1640 supplemented with 10% FBS and penicillin/streptomycin/glutamine was used as assay medium to prepare cell suspensions and dilutions.
- Serial dilutions of HLA-A2+ 293T cells were done in round-bottom 96-well plates, starting at 3.0 x 10 5 cells with 2-fold dilutions down.
- the APCs were then transferred to a 96- well flat-bottom white plate (Nunc #136102) in 40 m ⁇ and pulsed with 100 uM of NY-ESO-1 peptide for 2 hours.
- Reporter T cells were prepared in a suspension of 1 .25 x 10 6 cells/mL and 40 m ⁇ was added per well (5 x 10 4 cells/well). Plates containing the co-culture were incubated for 5 hours at 37°C/5% C0 2 Luciferase activity was then detected after the addition of ONE- GloTM (Promega, # E61 10) reagent and relative light units (RLUs) were measured on a
- TCRs concentration dependent manner as measured by AP-1 luciferase activity (FIG. 1 ).
- the specific activity of these TCRs were defined as the ratio of RLU to peptide pulsed APCs divided by the RLU to non-pulsed APCs.
- the specific activity of these four VelociTTM derived TCRs were considerably higher than the patient derived 1 G4 comparator TCR as well as its in vitro matured derivative, 1 13. (Table 4). Table 4.
- an associated potential off-target peptide was defined based on two criteria: A) the peptide is a 9-mer and is predicted to bind HLA-A2, and B) the peptide is similar to the target peptide based on sequence homology. Therefore, to predict potential off-target peptides associated with SLLMWITQC (NY-ESO-1 ; SEQ ID NO: 1 1 1 ) the following methodology was used.
- canonical human protein sequences were downloaded from the UniprotKB database (version September 2014) (Magrae, Michele, and UniProt Consortium. Database 201 1 (201 1 ): bar009) and all 9-mers were extracted. This resulted in 1 1 ,1 18,076 peptides from 20,014 protein sequences.
- the peptide sequences were then evaluated for sequence homology with the target peptide. For each peptide, its Degree of Similarity (DoS) was calculated to the target peptide.
- VelociTTM derived TCRs had no off-target activity.
- the in vitro matured TCR Comparator Clone 1 13 non-specifically reacted with HLA-A2+ 293T cells indicating that while this affinity-matured TCR has high binding affinity against HLA-A2/NY-ESO-1 complex (26 pM, as reported by Zhao et al, J Immunol. 2007 November 1 ; 179(9): 5845-5854), it was also nonspecifically activated by other peptides bound to HLA-A2.
- Nonspecific activation of human T cells by a recombinant TCR could lead to toxicity if administered as a therapy in humans.
- T cell receptors were generated against the NY-ESO-1 157-165 peptide (SLLMWITC (SEQ ID NO: 164)) loaded into HLA-A2 using the VelociT platform, as described above.
- SLLMWITC NY-ESO-1 157-165 peptide
- TCR001 was reformatted into a composite TCR structure wherein the human constant domain of the TCRa or TORb chain was substituted with the murine counterpart to increase TCR stability for the assay. The human variable domains remained intact.
- the mouse TRBC1 gene was used for the TORb chain.
- the TCR was cloned into a bicistronic construct using a pLVX lentiviral vector having an EF1 a promoter and the TCR chains linked by a 2A peptide linker in a single ORF (FIG. 3).
- Peptide bond skipping during the translation of the mRNA at the 3’ end of the 2A sequence produced two proteins: a TCRa chain-2A fusion and a T ⁇ Rb chain.
- the 2A element was preceded by a sequence encoding a furin cleavage site, which is represented as a black box in FIG. 3. [00337]
- the endogenous TRAC and TRBC1 /2 were gene edited to prevent their expression using
- sgRNAs TrueGuide Modified Synthetic guide RNAs (sgRNAs) that bound near the 5’ end of the first exon of the TRAC gene and both TRBC1 /2 genes were designed and are depicted below in Table 6. None of the sgRNA sequences were predicted to bind to the sequence of TCR001 .
- T cells Post-electroporation, an aliquot of T cells was cultured with IL-2 (100 U/mL) for 72 hours in cRPMI culture media when the loss of endogenous TCR expression was characterized by evaluating a decrease in cell surface CD3 expression (FIG. 4).
- the transduced T cells were expanded with CD3/CD28 microbeads and recombinant human IL-2 (100 ILI/mL) for 9 days.
- Exogenous TCR001 expression was then assessed by Dextramer staining and CD8+ T cells expressing the composite TCR were highly enriched by sorting to >99% purity (FIG. 5A).
- the sorted cells then were co-cultured with irradiated FI LA-mismatched PBMC, isolated from two normal healthy donors and mixed at a 1 :1 ratio, and an HLA-mismatched B-LCL cell line.
- the HLA-mismatched and irradiated PBMC and B-LCL stimulatory cells were combined at a 5:1 ratio, respectively.
- TCR001 After 10 days of post-sort expansion, an aliquot of expanding T cells was harvested, washed, and resuspended in cRPMI media. Two target cell lines were used to measure antigen- dependent cytolysis by TCR001 : an IM9 target cell line that expresses endogenous NY-ESO-1 protein, and an IM9 cell line engineered to overexpress single chain HLA-A2 presenting an NY- ESO-1 (157-165) peptide (designated IM9 ++ ).
- the IM9 ++ target cell line which maximized antigen density, was included as a precaution against the possibility that endogenous levels of HLA-A2 loaded with NY-ESO-1 (157-165) on IM9 cells would be insufficient to trigger TCR- mediated cytolytic activity.
- Two negative controls were established to investigate antigen specific TCR mediated killing: a K562 cell line that does not express NY-ESO-1 protein, and untransduced T cells that were expanded with anti-CD3/CD28 beads in the presence of 100 lU/mL human IL-2 and used as effector T cells.
- Each target and control cell line was harvested and loaded with calcein-AM dye. After calcein labeling, target cells were washed twice to remove residual calcein. Subsequently, T cells and target cells were co-cultured on a 96 well round bottom plate at various ratios and cultured at 37 °C for 2.5 hours when culture
- each cell line was cultured in the absence of effector T cells.
- target cell lines were cultured and lysed using cRPMI media that was supplemented to contain 1% TritonTM X-1 14 detergent.
- the relative calcein levels were measured using a Viktor X4 plate reader and percent cytotoxicity was calculated as ((Calcein Signal - Spontaneous Calcein Release)/(Calcein Maximum
- enriched and expanded T cells expressing TCR001 induced robust cytolysis of both IM9 cells (grey open circles) and IM9 ++ cells (open black circles), but not K562 cells (filled black circles) which lack NY-ESO-1 expression.
- Table 8 Measured cytolysis of NY-ESO-1 + tumor cell lines by untransduced and expanded polyclonal T cells.
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